Revistas
Autores:
López-Alcalá, J.; Gordon, A. (Autor de correspondencia); Trávez, A.; et al.
Revista:
JOURNAL OF BIOMEDICAL SCIENCE
ISSN:
1021-7770
BackgroundExcessive lipid accumulation in the adipose tissue in obesity alters the endocrine and energy storage functions of adipocytes. Adipocyte lipid droplets represent key organelles coordinating lipid storage and mobilization in these cells. Recently, we identified the small GTPase, Rab34, in the lipid droplet proteome of adipocytes. Herein, we have characterized the distribution, intracellular transport, and potential contribution of this GTPase to adipocyte physiology and its regulation in obesity. Methods 3T3-L1 and human primary preadipocytes were differentiated in vitro and Rab34 distribution and trafficking were analyzed using markers of cellular compartments. 3T3-L1 adipocytes were transfected with expression vectors and/or Rab34 siRNA and assessed for secretory activity, lipid accumulation and expression of proteins regulating lipid metabolism. Proteomic and protein interaction analyses were employed for the identification of the Rab34 interactome. These studies were combined with functional analysis to unveil the role played by the GTPase in adipocytes, with a focus on the actions conveyed by Rab34 interacting proteins. Finally, Rab34 regulation in response to obesity was also evaluated. Results Our results show that Rab34 localizes at the Golgi apparatus in preadipocytes. During lipid droplet biogenesis, Rab34 translocates from the Golgi to endoplasmic reticulum-related compartments and then reaches the surface of adipocyte lipid droplets. Rab34 exerts distinct functions related to its intracellular location. Thus, at the Golgi, Rab34 regulates cisternae integrity as well as adiponectin trafficking and oligomerization. At the lipid droplets, this GTPase controls lipid accumulation and lipolysis through its interaction with the E1-ubiquitin ligase, UBA1, which induces the ubiquitination and proteasomal degradation of the fatty acid transporter and member of Rab34 interactome, FABP5. Finally, Rab34 levels in the adipose tissue and adipocytes are regulated in response to obesity and related pathogenic insults (i.e., fibrosis). Conclusions Rab34 plays relevant roles during adipocyte differentiation, including from the regulation of the oligomerization (i.e., biological activity) and secretion of a major adipokine with insulin-sensitizing actions, adiponectin, to lipid storage and mobilization from lipid droplets. Rab34 dysregulation in obesity may contribute to the altered adipokine secretion and lipid metabolism that characterize adipocyte dysfunction in conditions of excess adiposity.
Revista:
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN:
1138-7548
Año:
2024
Vol.:
80
N°:
1
Págs.:
149 - 160
Bariatric surgery has become a recognized and effective procedure for treating obesity and type 2 diabetes (T2D). Our objective was to directly compare the caloric intake-independent effects of sleeve gastrectomy (SG) and single anastomosis duodenoileal bypass with SG (SADI-S) on glucose tolerance in rats with diet-induced obesity (DIO) and to elucidate the differences between bariatric surgery and caloric restriction.A total of 120 adult male Wistar rats with DIO and insulin resistance were randomly assigned to surgical (sham operation, SG, and SADI-S) and dietary (pair-feeding the amount of food eaten by animals undergoing the SG or SADI-S surgeries) interventions. Body weight and food intake were weekly monitored, and 6 weeks after interventions, fasting plasma glucose, oral glucose and insulin tolerance tests, plasma insulin, adiponectin, GIP, GLP-1, and ghrelin levels were determined.The body weight of SADI-S rats was significantly (p < 0.001) lower as compared to the sham-operated, SG, and pair-fed groups. Furthermore, SADI-S rats exhibited decreased whole body fat mass (p < 0.001), lower food efficiency rates (p < 0.001), and increased insulin sensitivity, as well as improved glucose and lipid metabolism compared to that of the SG and pair-fed rats.SADI-S was more effective than SG, or caloric restriction, in improving glycemic control and metabolic profile, with a higher remission of insulin resistance as well as long-term weight loss.
Revista:
EUROPEAN JOURNAL OF ENDOCRINOLOGY
ISSN:
0804-4643
Año:
2023
Vol.:
188
N°:
7
Págs.:
564 - 577
Background Growing evidence suggests the key role of ghrelin in the onset and progression of nonalcoholic fatty liver disease (NAFLD). The potential participation of ghrelin and the ghrelin receptor antagonist, LEAP-2, in the onset of liver fibrosis in patients with severe obesity and NAFLD through the regulation of TGF-& beta;1-induced hepatic stellate cell (HSC) activation was investigated. Methods Circulating (n = 179) and hepatic expression (n = 95) of ghrelin and LEAP-2 were measured in patients with severe obesity and available liver pathology analysis undergoing Roux-en-Y gastric bypass (RYGB). The effect of ghrelin isoforms and LEAP-2 on TGF-& beta;1-induced HSC activation, fibrogenic response, and contractile properties was evaluated in vitro in human LX-2 cells. Results Plasma and hepatic ghrelin were negatively associated, while LEAP-2 exhibited a positive association with liver fibrosis in patients with obesity and NAFLD. Six months after RYGB, hepatic function was improved and, although acylated ghrelin and LEAP-2 concentrations remained unchanged, both hormones were inversely related to post-surgical levels of profibrogenic factors TGF-& beta;1 and TIMP-1. Acylated ghrelin treatment reversed TGF-& beta;1-induced myofibroblast-like phenotype, collagen contractile properties, and the upregulation of factors involved in HSC activation and fibrogenesis via PI3K/Akt/mTOR pathway. Moreover, acylated ghrelin inhibited the mild HSC activation induced by LEAP-2. Conclusions Ghrelin is an anti-fibrogenic factor blocking HSC activation induced by the most potent fibrogenic cytokine, TGF-& beta;1, and LEAP-2. The imbalance between acylated ghrelin and ghrelin receptor antagonist LEAP-2 might contribute to maintain liver fibrosis in patients with obesity and NAFLD.
Revista:
CARDIOVASCULAR DIABETOLOGY
ISSN:
1475-2840
Año:
2023
Vol.:
22
N°:
1
Págs.:
240
ObjectiveTo assess how inaccurately the body mass index (BMI) is used to diagnose obesity compared to body fat percentage (BF%) measurement and to compare the cardiometabolic risk in children and adolescents with or without obesity according to BMI but with a similar BF%.MethodsA retrospective cross-sectional investigation was conducted including 553 (378 females/175 males) white children and adolescents aged 6-17 years, 197 with normal weight (NW), 144 with overweight (OW) and 212 with obesity (OB) according to BMI. In addition to BMI, BF% measured by air displacement plethysmography, as well as markers of cardiometabolic risk had been determined in the existing cohort.ResultsWe found that 7% of subjects considered as NW and 62% of children and adolescents classified as OW according to BMI presented a BF% within the obesity range. Children and adolescents without obesity by the BMI criterion but with obesity by BF% exhibited higher blood pressure and C-reactive protein (CRP) in boys, and higher blood pressure, glucose, uric acid, CRP and white blood cells count, as well as reduced HDL-cholesterol, in girls, similar to those with obesity by BMI and BF%. Importantly, both groups of subjects with obesity by BF% showed a similarly altered glucose homeostasis after an OGTT as compared to their NW counterparts.ConclusionsResults from the present study suggest increased cardiometabolic risk factors in children and adolescents without obesity according to BMI but with obesity based on BF%. Being aware of the difficulty in determining body composition in everyday clinical practice, our data show that its inclusion could yield clinically useful information both for the diagnosis and treatment of overweight and obesity.
Revista:
FRONTIERS IN IMMUNOLOGY
ISSN:
1664-3224
Año:
2023
Vol.:
14
Págs.:
1138316
Autores:
Oliveras-Canellas, N.; Moreno-Navarrete, J. M.; Lorenzo, P. M.; et al.
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2023
Vol.:
109
N°:
1
Págs.:
e145 - e154
Context Climate change and global warming have been hypothesized to influence the increased prevalence of obesity worldwide. However, the evidence is scarce. Objective We aimed to investigate how outside temperature might affect adipose tissue physiology and metabolic traits. Methods The expression of genes involved in thermogenesis/browning and adipogenesis were evaluated (through quantitative polymerase chain reaction) in the subcutaneous adipose tissue (SAT) from 1083 individuals recruited in 5 different regions of Spain (3 in the North and 2 in the South). Plasma biochemical variables and adiponectin (enzyme-linked immunosorbent assay) were collected through standardized protocols. Mean environmental outdoor temperatures were obtained from the National Agency of Meteorology. Univariate, multivariate, and artificial intelligence analyses (Boruta algorithm) were performed. Results The SAT expression of genes associated with browning (UCP1, PRDM16, and CIDEA) and ADIPOQ were significantly and negatively associated with minimum, average, and maximum temperatures. The latter temperatures were also negatively associated with the expression of genes involved in adipogenesis (FASN, SLC2A4, and PLIN1). Decreased SAT expression of UCP1 and ADIPOQ messenger RNA and circulating adiponectin were observed with increasing temperatures in all individuals as a whole and within participants with obesity in univariate, multivariate, and artificial intelligence analyses. The differences remained statistically significant in individuals without type 2 diabetes and in samples collected during winter. Conclusion Decreased adipose tissue expression of genes involved in browning and adiponectin with increased environmental temperatures were observed. Given the North-South gradient of obesity prevalence in these same regions, the present observations could have implications for the relationship of the obesity pandemic with global warming.
Revista:
FRONTIERS IN ENDOCRINOLOGY
ISSN:
1664-2392
Año:
2023
Vol.:
14
Págs.:
1185456
Introduction: Obesity contributes to ectopic fat deposition in non-adipose organs, including the pancreas. Pancreas steatosis associates with inflammation and beta-cell dysfunction, contributing to the onset of insulin resistance and type 2 diabetes. An improvement of pancreatic steatosis and indices of insulin resistance is observed following bariatric surgery, but the underlying mechanisms remain unknown. We sought to analyze whether guanylin (GUCA2A) and uroguanylin (GUCA2B), two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of pancreas fat accumulation after bariatric surgery. Methods: Pancreas steatosis, inflammation, islet number and area were measured in male Wistar rats with diet-induced obesity (n=125) subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by gastrectomized animals) interventions. The tissue distribution of guanylate cyclase C (GUCY2C) and the expression of the guanylin system were evaluated in rat pancreata by real-time PCR, Western-blot and immunohistochemistry. The effect of guanylin and uroguanylin on factors involved in insulin secretion and lipogenesis was determined in vitro in RIN-m5F beta-cells exposed to lipotoxic conditions. Results: Sleeve gastrectomy reduced pancreas steatosis and inflammation and improved insulin sensitivity and synthesis. An upregulation of GUCA2A and GUCY2C, but not GUCA2B, was observed in pancreata from rats with dietinduced obesity one month after sleeve gastrectomy. Interestingly, both guanylin and uroguanylin diminished the lipotoxicity in palmitate-treated RIN-m5F beta-cells, evidenced by lower steatosis and downregulated lipogenic factors Srebf1, Mogat2 and Dgat1. Both guanylin peptides reduced insulin synthesis (Ins1 and Ins2) and release from RIN-m5F beta-cells, but only guanylin upregulated Wnt4, a factor that controls beta-cell proliferation and function. Discussion: Together, sleeve gastrectomy reduced pancreatic steatosis and improved beta-cell function. Several mechanisms, including the modulation of inflammation and lipogenesis as well as the upregulation of GUCA2A in the pancreas, might explain this beneficial effect of bariatric surgery.
Autores:
Aguas-Ayesa, M.; Yárnoz-Esquiroz, P.; Olazarán, L.; et al.
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2023
Vol.:
15
N°:
22
Págs.:
4824
Unhealthy dietary habits and sedentarism coexist with a rising incidence of excess weight and associated comorbidities. We aimed to analyze the dietary and drinking patterns of patients with excess weight, their main characteristics, plausible gender differences and impact on cardiometabolic risk factors, with a particular focus on the potential contribution of beer consumption. Data from 200 consecutive volunteers (38 +/- 12 years; 72% females) living with overweight or class I obesity attending the obesity unit to lose weight were studied. Food frequency questionnaires and 24 h recalls were used. Reduced-rank regression (RRR) analysis was applied to identify dietary patterns (DPs). Anthropometry, total and visceral fat, indirect calorimetry, physical activity level, comorbidities and circulating cardiometabolic risk factors were assessed. Study participants showed high waist circumference, adiposity, insulin resistance, dyslipidemia, pro-inflammatory adipokines and low anti-inflammatory factors like adiponectin and interleukin-4. A low-fiber, high-fat, energy-dense DP was observed. BMI showed a statistically significant (p < 0.05) correlation with energy density (r = 0.80) as well as percentage of energy derived from fat (r = 0.61). Excess weight was associated with a DP low in vegetables, legumes and whole grains at the same time as being high in sweets, sugar-sweetened beverages, fat spreads, and processed meats. RRR analysis identified a DP characterized by high energy density and saturated fat exhibiting negative loadings (>-0.30) for green leafy vegetables, legumes, and fruits at the same time as showing positive factor loadings (>0.30) for processed foods, fat spreads, sugar-sweetened beverages, and sweets. Interestingly, for both women and men, wine represented globally the main source of total alcohol intake (p < 0.05) as compared to beer and distillates. Beer consumption cannot be blamed as the main culprit of excess weight. Capturing the DP provides more clinically relevant and useful information. The focus on consumption of single nutrients does not resemble real-world intake behaviors.
Autores:
González-Rellán, M. J.; Novoa, E.; da Silva Lima, N.; et al.
Revista:
GUT
ISSN:
0017-5749
Año:
2023
Vol.:
72
N°:
3
Págs.:
472 - 483
Objective p63 is a transcription factor within the p53 protein family that has key roles in development, differentiation and prevention of senescence, but its metabolic actions remain largely unknown. Herein, we investigated the physiological role of p63 in glucose metabolism. Design We used cell lines and mouse models to genetically manipulate p63 in hepatocytes. We also measured p63 in the liver of patients with obesity with or without type 2 diabetes (T2D). Results We show that hepatic p63 expression is reduced on fasting. Mice lacking the specific isoform TAp63 in the liver (p63LKO) display higher postprandial and pyruvate-induced glucose excursions. These mice have elevated SIRT1 levels, while SIRT1 knockdown in p63LKO mice normalises glycaemia. Overexpression of TAp63 in wild-type mice reduces postprandial, pyruvate-induced blood glucose and SIRT1 levels. Studies carried out in hepatocyte cell lines show that TAp63 regulates SIRT1 promoter by repressing its transcriptional activation. TAp63 also mediates the inhibitory effect of insulin on hepatic glucose production, as silencing TAp63 impairs insulin sensitivity. Finally, protein levels of TAp63 are reduced in obese persons with T2D and are negatively correlated with fasting glucose and homeostasis model assessment index. Conclusions. These results demonstrate that p63 physiologically regulates glucose homeostasis.
Autores:
Gonzalez-Rellan, M. J.; Parracho, T.; Heras, V.; et al.
Revista:
MOLECULAR METABOLISM
ISSN:
2212-8778
Año:
2023
Vol.:
75
Págs.:
101776
Objective: O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD.
Methods: We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD.
Results: O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD.
Conclusions: These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2023
Vol.:
24
N°:
4
Págs.:
3412
Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2 , Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4( ?)C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2 , Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy.
Revista:
CANCERS
ISSN:
2072-6694
Año:
2023
Vol.:
15
N°:
4
Págs.:
1038
Simple Summary Netrin-1 (NTN-1) regulates obesity-associated low-grade inflammation, being also involved in the control of cell migration and proliferation. We aim to study whether excess visceral adipose tissue in patients with obesity and colon cancer is associated with increased NTN1 and the expression levels of its main receptors, promoting an inflammatory microenvironment that favours colon cancer development. Increased expression levels of NTN1 and its receptor NEO1 in the visceral adipose tissue from patients with obesity and colon cancer together with elevated DCC and UNC5B mRNA levels in patients with colon cancer were found. Moreover, the treatment of colorectal cancer cells with NTN-1 and with the adipocyte-derived secretome obtained from patients with obesity increased the migration of colorectal cancer cells. These results suggest that NTN-1 plays an important role in obesity-associated colon cancer development. Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.
Autores:
Gonzalez-Rellan, M. J.; Fernández, U.; Parracho, T.; et al.
Revista:
CELL METABOLISM
ISSN:
1550-4131
Año:
2023
Vol.:
35
N°:
9
Págs.:
1630 - 1645
Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2023
Vol.:
15
N°:
1
Págs.:
73
Biological sex and aging impact obesity development and type 2 diabetes, changing the secretion of leptin and adiponectin. The balance between these factors has been propounded as a reliable biomarker of adipose tissue dysfunction. Our proposal was to study sexual differences and aging on the adiponectin/leptin (Adpn/Lep) ratio in order to acquire a broader view of the impact of consuming an high-fat diet (HFD) on energy metabolism according to sex and age. Male and female C57BL/6J mice were fed a normal chow diet or an HFD for 12 or 32 weeks (n = 7-10 per group) and evolution of body weight, food intake and metabolic profile were registered. The HFD triggered an increase in body weight (p < 0.001), body weight gain (p < 0.01) and adiposity index (p < 0.01) in both sexes at 32 weeks of age, but female mice fed the HFD exhibited these changes to a significantly lower extent than males. Aged female mice showed an increase (p < 0.01) in the Adpn/Lep ratio, which was negatively correlated with body weight gain, changes in different fat depots and insulin resistance. Females were more metabolically protected from obesity development and its related comorbidities than males regardless of age, making the Adpn/Lep ratio a relevant factor for body composition and glucose metabolism.
Revista:
REVIEWS IN ENDOCRINE AND METABOLIC DISORDERS
ISSN:
1389-9155
Año:
2023
Vol.:
24
N°:
5
Págs.:
795 - 807
Obesity is a complex disease that relapses frequently and associates with multiple complications that comprise a worldwide health priority because of its rising prevalence and association with numerous complications, including metabolic disorders, mechanic pathologies, and cancer, among others. Noteworthy, excess adiposity is accompanied by chronic inflammation, oxidative stress, insulin resistance, and subsequent organ dysfunction. This dysfunctional adipose tissue is initially stored in the visceral depot, overflowing subsequently to produce lipotoxicity in ectopic depots like liver, heart, muscle, and pancreas, among others. People living with obesity need a diagnostic approach that considers an exhaustive pathophysiology and complications assessment. Thus, it is essential to warrant a holistic diagnosis and management that guarantees an adequate health status, and quality of life. The present review summarizes the different complications associated with obesity, at the same time, we aim to fostering a novel framework that enhances a patient-centered approach to obesity management in the precision medicine era.
Autores:
Christou, G. A.; Andriopoulou, C. E.; Liakopoulou, A.; et al.
Revista:
HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM
ISSN:
1109-3099
Año:
2023
Vol.:
22
N°:
2
Págs.:
321 - 330
PurposeAdipokines produced by adipose tissue have been found to be involved in the pathophysiology of metabolic and cardiovascular diseases. We aimed to investigate the relationships of resistin, retinol-binding protein 4 (RBP4) and adiponectin produced by epicardial adipose tissue with coronary artery disease (CAD) and cardiac structure and function.MethodsForty-one non-diabetic males scheduled for cardiothoracic surgery were examined. Anthropometric measurements, echocardiography, coronary angiography, and blood analysis were performed preoperatively. We measured the serum levels of resistin, RBP4, and adiponectin and their mRNA expression in thoracic subcutaneous adipose tissue and two epicardial adipose tissue samples, one close to left anterior descending artery (LAD) (resistin-LAD, RBP4-LAD, adiponectin-LAD), and another close to the right coronary artery (RCA) (resistin-RCA, RBP4-RCA, adiponectin-RCA).ResultsLeft ventricular (LV) ejection fraction correlated negatively with adiponectin-LAD (rho = - 0.390, p = 0.025). The ratio of early to late diastolic transmitral flow velocity, as an index of LV diastolic function, correlated negatively with resistin-LAD (rho = - 0.529, p = 0.024) and RBP4-LAD (rho = - 0.458, p = 0.049). There was no difference in epicardial adipose tissue mRNA expression of resistin, RBP4, and adiponectin between individuals with CAD and those without CAD. When we compared the individuals with CAD in the LAD with those without CAD in the LAD, there was no difference in resistin-LAD, RBP4-LAD, and adiponectin-LAD. There was no difference in resistin-RCA, RBP4-RCA, and adiponectin-RCA between the individuals with CAD in the RCA and those without CAD in the RCA.ConclusionElevation of epicardial adipose tissue mRNA expression of adiponectin was associated with LV systolic dysfunction, while that of both resistin and RBP4 was linked to LV diastolic dysfunction.
Revista:
METABOLISM-CLINICAL AND EXPERIMENTAL
ISSN:
0026-0495
Año:
2023
Vol.:
147
Págs.:
155663
Background: The biological mediators supporting the resolution of liver steatosis, inflammation and fibrosis after bariatric surgery in patients with obesity and NAFLD remain unclear. We sought to analyze whether uroguanylin and guanylin, two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of obesity-associated NAFLD after bariatric surgery. Methods: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 214 participants undergoing bariatric surgery with biopsy-proven NAFLD diagnosis. Pathways involved in lipid metabolism, mitochondrial network and fibrogenesis were evaluated in liver biopsies (n = 137). The effect of guanylin and uroguanylin on these metabolic functions was assessed in HepG2 hepatocytes and LX-2 hepatic stellate cells (HSC) under lipotoxic and profibrogenic conditions.Results: Plasma and hepatic expression of GUCA2B were decreased in obesity-associated NAFLD. Both GUCA2A and GUCA2B levels were increased after sleeve gastrectomy and Roux-en-Y gastric bypass in parallel to the improved liver function. The liver of patients with type 2 diabetes showed impaired mitochondrial & beta;-oxidation, biogenesis, dynamics as well as increased fibrosis. Uroguanylin diminished the lipotoxicity in palmitate-treated HepG2 hepatocytes, evidenced by decresased steatosis and lipogenic factors, as well as increased mitochondrial network expression, AMPK-induced & beta;-oxidation and oxygen consumption rate. Additionally, uroguanylin, but not guanylin, reversed HSC myofibroblast transdifferentiation as well as fibrogenesis after TGF-& beta;1 stimulation.Conclusions: Uroguanylin constitutes a protective factor against lipotoxicity, mitochondrial dysfunction and fibrosis. Increased GUCA2B levels might contribute to improve liver injury in patients with obesity-associated NAFLD after bariatric surgery.
Autores:
Yárnoz-Esquiroz, P.; Olazarán, L.; Aguas-Ayesa, M.; et al.
Revista:
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN:
0014-2972
Año:
2022
Vol.:
52
N°:
7
Págs.:
e13811
Academic medicine fosters research that moves from discovery to translation, at the same time as promoting education of the next generation of professionals. In the field of obesity, the supposed integration of knowledge, discovery and translation research to clinical care is being particularly hampered. The classification of obesity based on the body mass index does not account for several subtypes of obesity. The lack of a universally shared definition of "obesities" makes it impossible to establish the real burden of the different obesity phenotypes. The individual's genotype, adipotype, enterotype and microbiota interplays with macronutrient intake, appetite, metabolism and thermogenesis. Further investigations based on the concept of differently diagnosed "obesities" are required.
Revista:
FRONTIERS IN MEDICINE
ISSN:
2296-858X
Año:
2022
Vol.:
9
Págs.:
1023583
BackgroundTo better understand the patient's heterogeneity in fatty liver disease (FLD), metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed by international experts as a new nomenclature for nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the cardiovascular risk, assessed through coronary artery calcium (CAC) and epicardial adipose tissue (EAT), of patients without FLD and patients with FLD and its different subtypes. MethodsCross sectional study of 370 patients. Patients with FLD were divided into 4 groups: FLD without metabolic dysfunction (non-MD FLD), MAFLD and the presence of overweight/obesity (MAFLD-OW), MAFLD and the presence of two metabolic abnormalities (MAFLD-MD) and MAFLD and the presence of T2D (MAFLD-T2D). MAFLD-OW included two subgroups: metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUHO). The patients without FLD were divided into 2 groups: patients without FLD and without MD (non-FLD nor MD; reference group) and patients without FLD but with MD (non-FLD with MD). EAT and CAC (measured through the Agatston Score) were determined by computed tomography. ResultsCompared with the reference group (non-FLD nor MD), regarding EAT, patients with MAFLD-T2D and MAFLD-MUHO had the highest risk for CVD (OR 15.87, 95% CI 4.26-59.12 and OR 17.60, 95% CI 6.71-46.20, respectively), patients with MAFLD-MHO were also at risk for CVD (OR 3.62, 95% CI 1.83-7.16), and patients with non-MD FLD did not have a significantly increased risk (OR 1.77; 95% CI 0.67-4.73). Regarding CAC, patients with MAFLD-T2D had an increased risk for CVD (OR 6.56, 95% CI 2.18-19.76). Patients with MAFLD-MUHO, MAFLD-MHO and non-MD FLD did not have a significantly increased risk compared with the reference group (OR 2.54, 95% CI 0.90-7.13; OR 1.84, 95% CI 0.67-5.00 and OR 2.11, 95% CI 0.46-9.74, respectively). ConclusionMAFLD-T2D and MAFLD-OW phenotypes had a significant risk for CVD. MAFLD new criteria reinforced the importance of identifying metabolic phenotypes in populations as it may help to identify patients with higher CVD risk and offer a personalized therapeutic management in a primary prevention setting.
Revista:
ACTA BIOMATERIALIA
ISSN:
1742-7061
Año:
2022
Vol.:
141
Págs.:
264 - 279
Biomechanical properties of adipose tissue (AT) are closely involved in the development of obesity associated comorbidities. Bariatric surgery (BS) constitutes the most effective option for a sustained weight loss in addition to improving obesity-associated metabolic diseases including type 2 diabetes (T2D). We aimed to determine the impact of weight loss achieved by BS and caloric restriction (CR) on the biomechanical properties of AT. BS but not CR changed the biomechanical properties of epididymal white AT (EWAT) from a diet-induced obesity rat model, which were associated with metabolic improvements. We found decreased gene expression levels of collagens and Lox together with increased elastin and Mmps mRNA levels in EWAT after BS, which were also associated with the biomechanical properties. Moreover, an increased blood vessel density was observed in EWAT after surgery, confirmed by an up regulation of Acta2 and Antxr1 gene expression levels, which was also correlated with the biomechanical properties. Visceral AT from patients with obesity showed increased stiffness after tensile tests compared to the EWAT from the animal model. This study uncovers new insights into EWAT adaptation after BS with decreased collagen crosslink and synthesis as well as an increased degradation together with enhanced blood vessel density providing, simultaneously, higher stiffness and more ductility.
Statement of Significance
Biomechanical properties of the adipose tissue (AT) are closely involved in the development of obesity associated comorbidities. In this study, we show for the first time that biomechanical properties of AT determined by E , UTS and strain at UTS are decreased in obesity, being increased after bariatric surgery by the promotion of ECM remodelling and neovascularization. Moreover, these changes in biomechanical properties are associated with improvements in metabolic homeostasis. Consistently, a better characterization of the plasticity and biomechanical properties of the AT after bariatric surgery opens up a new field for the development of innovative strategies for the reduction of fibrosis and inflammation in AT as well as to better understand obesity and its associated comorbidities.
Autores:
Donini, L. M. (Autor de correspondencia); Busetto, L.; Bischoff, S. C.; et al.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2022
Vol.:
15
N°:
3
Págs.:
321 - 335
Introduction: Loss of skeletal muscle mass and function (sarcopenia) is common in individuals with obesity due to metabolic changes associated with a sedentary lifestyle, adipose tissue derangements, comorbidities (acute and chronic diseases), and during the ageing process. Co-existence of excess adiposity and low muscle mass/function is referred to as sarcopenic obesity (SO), a condition increasingly recognized for its clinical and functional features that negatively influence important patient-centred outcomes. Effective prevention and treatment strategies for SO are urgently needed, but efforts are hampered by the lack of an universally established SO Definition and diagnostic criteria. Resulting inconsistencies in the literature also negatively affect the ability to define prevalence as well as clinical relevance of SO for negative health outcomes. Aims and methods: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) launched an initiative to reach expert consensus on a Definition and diagnostic criteria for SO. The jointly appointed international expert panel proposes that SO is defined as the co-existence of excess adiposity and low muscle mass/function. The diagnosis of SO should be considered in at-risk individuals who screen positive for a co-occurring elevated body mass index or waist circumference, and markers of low skeletal muscle mass and function (risk factors, clinical symptoms, or validated questionnaires). Diagnostic procedures should initially include assessment of skeletal muscle function, followed by assessment of body composition where presence of excess adiposity and low skeletal muscle mass or related body compartments confirm the diagnosis of SO. Individuals with SO should be further stratified into Stage I in the absence of clinical complications, or Stage II if cases are associated with complications linked to altered body composition or skeletal muscle dysfunction. Conclusions: ESPEN and EASO, as well as the expert international panel, advocate that the proposed SO Definition and diagnostic criteria be implemented into routine clinical practice. The panel also encourages prospective studies in addition to secondary analysis of existing datasets, to study the predictive value, treatment efficacy, and clinical impact of this SO definition.
Autores:
Donini, L. M. (Autor de correspondencia); Busetto, L.; Bischoff, S. C.; et al.
Revista:
CLINICAL NUTRITION
ISSN:
0261-5614
Año:
2022
Vol.:
41
N°:
4
Págs.:
990 - 1000
Introduction: Loss of skeletal muscle mass and function (sarcopenia) is common in individuals with obesity due to metabolic changes associated with a sedentary lifestyle, adipose tissue derangements, comorbidities (acute and chronic diseases), and during the ageing process. Co-existence of excess adiposity and low muscle mass/function is referred to as sarcopenic obesity (SO), a condition increasingly recognized for its clinical and functional features that negatively influence important patient-centred outcomes. Effective prevention and treatment strategies for SO are urgently needed, but efforts are hampered by the lack of an universally established SO Definition and diagnostic criteria. Resulting inconsistencies in the literature also negatively affect the ability to define prevalence as well as clinical relevance of SO for negative health outcomes. Aims and methods: The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) launched an initiative to reach expert consensus on a Definition and diagnostic criteria for SO. The jointly appointed international expert panel proposes that SO is defined as the co-existence of excess adiposity and low muscle mass/function. The diagnosis of SO should be considered in at-risk individuals who screen positive for a co-occurring elevated body mass index or waist circumference, and markers of low skeletal muscle mass and function (risk factors, clinical symptoms, or validated questionnaires). Diagnostic procedures should initially include assessment of skeletal muscle function, followed by assessment of body composition where presence of excess adiposity and low skeletal muscle mass or related body compartments confirm the diagnosis of SO. Individuals with SO should be further stratified into Stage I in the absence of clinical complications, or Stage II if cases are associated with complications linked to altered body composition or skeletal muscle dysfunction. Conclusions: ESPEN and EASO, as well as the expert international panel, advocate that the proposed SO Definition and diagnostic criteria be implemented into routine clinical practice. The panel also encourages prospective studies in addition to secondary analysis of existing datasets, to study the predictive value, treatment efficacy, and clinical impact of this SO definition.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2022
Vol.:
23
N°:
16
Págs.:
9222
Dysfunctional adipose tissue (AT) in the context of obesity leads to chronic inflammation together with an altered extracellular matrix (ECM) remodelling, favouring cancer development and progression. Recently, the influence of dermatopontin (DPT) in AT remodelling and inflammation has been proposed. We aimed to evaluate the role of DPT in the development of obesity-associated colon cancer (CC). Samples obtained from 73 subjects [26 lean (LN) and 47 with obesity (OB)] were used in a case-control study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (42 without CC and 31 with CC). In vitro studies in the adenocarcinoma HT-29 cell line were performed to analyse the impact of pro- and anti-inflammatory mediators on the transcript levels of DPT as well as the effect of DPT on ECM remodelling and inflammation. Although obesity increased (p < 0.05) the circulating levels of DPT, its concentrations were significantly decreased (p < 0.05) in patients with CC. Gene expression levels of DPT in the colon from patients with CC were downregulated and, oppositely, a tendency towards increased mRNA levels in visceral AT was found. We further showed that DPT expression levels in HT-29 cells were enhanced (p < 0.05) by inflammatory factors (LPS, TNF-alpha and TGF-beta), whereas the anti-inflammatory IL-4 decreased (p < 0.05) its expression levels. We also demonstrated that DPT upregulated (p < 0.05) the mRNA of key molecules involved in ECM remodelling (COL1A1, COL5A3, TNC and VEGFA) whereas decorin (DCN) expression was downregulated (p < 0.05) in HT-29 cells. Finally, we revealed that the adipocyte-conditioned medium obtained from volunteers with OB enhanced (p < 0.01) the expression of DPT in HT-29 and Caco-2 cells. The decreased circulating and expression levels of DPT in the colon together with the tendency towards increased levels in visceral AT in patients with CC and its influence on the expression of ECM proteins suggest a possible role of DPT in the OB-associated CC.
Autores:
Liu, Q.; Reed, M.; Zhu, H.; et al.
Revista:
GENOMICS
ISSN:
0888-7543
Año:
2022
Vol.:
114
N°:
5
Págs.:
110474
Background: It has become increasingly important to identify molecular markers for accurately diagnosing prostate cancer (PCa) stages between localized PCa (LPC) and locally advanced PCa (LAPC). However, there is a lack of profiling both epigenome-wide DNA methylation and transcriptome for the same patients with PCa at different stages. This study aims to identify epitranscriptomic biomarkers screened in the periprostatic (PP) adipose tissue for predicting LPC and LAPC. Methods: We profiled gene expression and DNA methylation of 10 PCa patients' PP adipose tissue (4 LPC and 6 LAPC). Differential analysis was used to identify differentially methylated CpG sites and expressed genes. An integrative analysis of the microarray gene expression profiles and DNA methylation profiles was conducted using LASSO (least absolute shrinkage and selection operator) between each studied gene and the CpG sites in their promoter region. This epitranscriptomic signature was constructed by combining the association and differential analyses. The signature was then refined using the genetic mutation data of > 1500 primary PCa and metastasis PCa samples from 4 different studies. We determined genes that were the most significantly affected by mutations. Machine learning models were built to evaluate the classification ability of the identified signature using the gene expression profiles from three external cohorts. Results: From the LASSO-based association analysis, we identified 56 genes presenting significant anti-correlation between the expression level and the methylation level of at least one CpG site in the promoter region (p-value < 5 x 10(-8)). From the differential analysis, we detected 16,405 downregulated genes and 9485 genes containing at least one hypermethylated CpG site. We identified 30 genes that showed anti-correlation, down-regulation and hyper-methylation simultaneously. Using genetic mutation data, we determined that 6 of the 30 genes showed significant differences (adjusted p-value < 0.05) in mutation frequencies between the primary PCa and metastasis PCa samples. The identified 30 genes performed well in distinguishing PCa patients with metastasis from PCa patient without metastasis (area under the receiver operating characteristic curve (AUC) = 0.81). The gene signature also performed well in distinguishing PCa patients with high risk of progression from PCa patients with low risk of progression (AUC = 0.88). Conclusions: We established an integrative framework to identify differentially expressed genes with an aberrant methylation pattern on PP adipose tissue that may represent novel candidate molecular markers for distinguishing between LPC and LAPC.
Revista:
METABOLISM-CLINICAL AND EXPERIMENTAL
ISSN:
0026-0495
Año:
2022
Vol.:
128
Págs.:
155119
Background: The biological mediators supporting long-term weight loss and changes in dietary choice behaviour after sleeve gastrectomy remain unclear. Guanylin and uroguanylin are gut hormones involved in the regulation of satiety, food preference and adiposity. Thus, we sought to analyze whether the guanylin system is involved in changes in food preference after sleeve gastrectomy in obesity.
Methods: Proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were determined in patients with severe obesity (n = 41) as well as in rats with diet-induced obesity (n = 48), monogenic obesity (Zucker fa/fa) (n = 18) or in a food choice paradigm (normal diet vs high-fat diet) (n = 16) submitted to sleeve gastrectomy. Lingual distribution and expression of guanylins (GUCA2A and GUCA2B) and their receptor GUCY2C as well as the fatty acid receptor CD36 were evaluated in the preclinical models.
Results: Circulating concentrations of GUCA2A and GUCA2B were increased after sleeve gastrectomy in patients with severe obesity as well as in rats with diet-induced and monogenic (fa/fa) obesity. Interestingly, the lower dietary fat preference observed in obese rats under the food choice paradigm as well as in patients with obesity after sleeve gastrectomy were negatively associated with post-surgical GUCA2B levels. Moreover, sleeve gastrectomy upregulated the low expression of GUCA2A and GUCA2B in taste bud cells of tongues from rats with diet induced and monogenic (fa/fa) obesity in parallel to a downregulation of the lingual lipid sensor CD36.
Conclusions: The increased circulating and lingual GUCA2B after sleeve gastrectomy suggest an association between the uroguanylin-GUCY2C endocrine axis and food preference through the regulation of gustatory responses. (c) 2022 Elsevier Inc. All rights reserved.
Autores:
Baenas, I.; Etxandi, M.; Munguia, L.; et al.
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2022
Vol.:
14
N°:
1
Págs.:
100
Background. The COVID-19 lockdown has had a significant impact on mental health. Patients with eating disorders (ED) have been particularly vulnerable. Aims. (1) To explore changes in eating-related symptoms and general psychopathology during lockdown in patients with an ED from various European and Asian countries; and (2) to assess differences related to diagnostic ED subtypes, age, and geography. Methods. The sample comprised 829 participants, diagnosed with an ED according to DSM-5 criteria from specialized ED units in Europe and Asia. Participants were assessed using the COVID-19 Isolation Scale (CIES). Results. Patients with binge eating disorder (BED) experienced the highest impact on weight and ED symptoms in comparison with other ED subtypes during lockdown, whereas individuals with other specified feeding and eating disorders (OFSED) had greater deterioration in general psychological functioning than subjects with other ED subtypes. Finally, Asian and younger individuals appeared to be more resilient. Conclusions. The psychopathological changes in ED patients during the COVID-19 lockdown varied by cultural context and individual variation in age and ED diagnosis. Clinical services may need to target preventive measures and adapt therapeutic approaches for the most vulnerable patients.
Autores:
Yarnoz-Esquiroz, P. (Autor de correspondencia); Chopitea, Ana; Olazarán, L.; et al.
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2022
Vol.:
14
N°:
13
Págs.:
2754
Many studies have demonstrated that malnutrition has a negative impact on quality of life and mortality in patients with cancer. During the SARS-CoV-2 lockdown, dietary intake changes were detected in the Spanish population, reflecting an increase in the consumption of fruit, bread, flours, and eggs. The present study analyzed the nutritional status of 728 patients with cancer admitted once the SARS-CoV-2 lockdown finished, comparing it with the previous year as well as with mortality rates. The Malnutrition Universal Screening Tool (MUST) was applied in the first 24 h after admission. Age, gender, days of stay, circulating concentrations of albumin, cholesterol, C-reactive protein (CRP), lymphocytes, prealbumin, and mortality data were analyzed. Patients with cancer admitted between June and December of 2020 exhibited no statistical differences in BMI, age, or gender as compared to patients admitted in 2019. Statistically significant differences in nutritional status (p < 0.05), albumin (p < 0.001), and CRP (p = 0.005) levels regarding lockdown were observed in relation with a small non-significant reduction in mortality. In conclusion, following the SARS-CoV-2 lockdown, an improved nutritional status in cancer patients at admission was observed with a decrease in the percentage of weight loss and CRP levels together with an increase in albumin levels compared to oncological patients admitted the previous year.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2022
Vol.:
23
N°:
19
Págs.:
11641
Bariatric surgery has been recognized as the safest and most effective procedure for controlling type 2 diabetes (T2D) and obesity in carefully selected patients. The aim of the present study was to compare the effects of Sleeve Gastrectomy (SG) and Single Anastomosis Duodenoileal Bypass with SG (SADI-S) on the metabolic profile of diet-induced obese rats. A total of 35 four-week-old male Wistar rats were submitted to surgical interventions (sham operation, SG and SADI-S) after 4 months of being fed a high-fat diet. Body weight, metabolic profile and the expression of molecules involved in the control of subcutaneous white (SCWAT), brown (BAT) and beige (BeAT) adipose tissue function were analyzed. SADI-S surgery was associated with significantly decreased amounts of total fat pads (p < 0.001) as well as better control of lipid and glucose metabolism compared to the SG counterparts. An improved expression of molecules involved in fat browning in SCWAT and in the control of BAT and BeAT differentiation and function was observed following SADI-S. Together, our findings provide evidence that the enhanced metabolic improvement and their continued durability after SADI-S compared to SG rely, at least in part, on the improvement of the BeAT phenotype and function.
Revista:
FRONTIERS IN IMMUNOLOGY
ISSN:
1664-3224
Año:
2022
Vol.:
13
Págs.:
832185
Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36 gamma, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis. Plasma IL-36 gamma was measured in 91 participants in a case-control study and the effect of weight loss was evaluated in 31 patients with severe obesity undergoing bariatric surgery. Gene expression levels of IL36G and its receptor were analyzed in relevant human metabolic tissues. The effect of inflammatory factors and IL-36 gamma was determined in vitro in human adipocytes and macrophages. We found, for the first time, that the increased (P<0.05) circulating levels of IL-36 gamma in patients with obesity decreased (P<0.001) after weight and fat loss achieved by Roux-en-Y gastric bypass and that gene expression levels of IL36G were upregulated in the visceral AT (P<0.05) and in the peripheral blood mononuclear cells (P<0.01) from patients with obesity. We also demonstrated increased (P<0.05) expression levels of Il36g in the epididymal AT from diet-induced obese mice. IL36G was significantly enhanced (P<0.001) by LPS in human adipocytes and monocyte-derived macrophages, while no changes were found after the incubation with anti-inflammatory cytokines. The addition of IL-36 gamma for 24 h strongly induced (P<0.01) its own expression as well as key inflammatory and chemoattractant factors with no changes in genes associated with fibrosis. Furthermore, adipocyte-conditioned media obtained from patients with obesity increased (P<0.01) the release of IL-36 gamma and the expression (P<0.05) of cathepsin G (CTSG) in monocyte-derived macrophages. These findings provide, for the first time, evidence about the properties of IL-36 gamma in the regulation of AT-chronic inflammation, emerging as a link between AT biology and the obesity-associated comorbidities.
Revista:
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN:
0014-2972
Año:
2022
Vol.:
52
N°:
5
Págs.:
e13723
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2022
Vol.:
14
N°:
20
Págs.:
4372
Netrin (NTN)-1 exhibits pro- and anti-inflammatory roles in different settings, playing important roles in the obesity-associated low-grade chronic inflammation. We aimed to determine the impact of NTN-1 on obesity and obesity-associated type 2 diabetes, as well as its role in visceral adipose tissue (VAT) inflammation. A total of 91 subjects were enrolled in this case-control study. Circulating levels of NTN-1 and its receptor neogenin (NEO)-1 were determined before and after weight loss achieved by caloric restriction and bariatric surgery. mRNA levels of NTN1 and NEO1 were assessed in human VAT, liver, and peripheral blood mononuclear cells. In vitro studies in human visceral adipocytes and human monocytic leukemia cells (THP-1)-derived macrophages were performed to analyze the impact of inflammation-related mediators on the gene expression levels of NTN1 and its receptor NEO1 as well as the effect of NTN-1 on inflammation. Increased (p < 0.001) circulating concentrations of NTN-1 in obesity decreased (p < 0.05) after diet-induced weight loss being also associated with a reduction in glucose (p < 0.01) and insulin levels (p < 0.05). Gene expression levels of NTN1 and NEO1 were upregulated (p < 0.05) in the VAT from patients with obesity with the highest expression in the stromovascular fraction cells compared with mature adipocytes (p < 0.01). NTN1 expression levels were enhanced (p < 0.01) under hypoxia and by inflammatory factors in both adipocytes and macrophages. Adipocyte-conditioned media strongly upregulated (p < 0.001) the mRNA levels of NTN1 in macrophages. The treatment of adipocytes with NTN-1 promoted the upregulation (p < 0.05) of pro-inflammatory and chemotactic molecules as well as its receptor NEO1. Collectively, these findings suggest that NTN-1 regulates VAT chronic inflammation and insulin resistance in obesity.
Revista:
JOURNAL OF INFLAMMATION RESEARCH
ISSN:
1178-7031
Año:
2022
Vol.:
15
Págs.:
1331 - 1345
Background: Excess adiposity leads to a dysfunctional adipose tissue that contributes to the development of obesity-associated comorbidities such as type 2 diabetes (T2D). Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring antagonist of the IL-1 receptor with anti-inflammatory properties. The aim of the present study was to compare the circulating concentrations of IL-1RA and its mRNA expression in visceral adipose tissue (VAT) in subjects with normal weight (NW), obesity with normoglycemia (OB-NG), or obesity with impaired glucose tolerance or T2D (OB-IGT&T2D) and to analyze the effect of changes in body fat percentage (BF%) on IL-1RA levels. Methods: Serum concentrations of IL-1RA were measured in 156 volunteers. Expression of IL1RN mRNA in VAT obtained from 36 individuals was determined. In addition, the concentrations of IL-1RA were measured before and after weight gain as well as weight loss following a dietetic program or Roux-en-Y gastric bypass (RYGB). Results: Serum levels of IL-1RA were significantly increased in individuals with obesity, being further increased in the OBIGT&T2D group (NW 440 +/- 316, OB-NG 899 +/- 562, OB-IGT&T2D 1265 +/- 739 pg/mL; P<0.001) and associated with markers of inflammation and fatty liver. IL1RN mRNA expression in VAT was significantly increased in the OB-IGT&T2D group and correlated in the global cohort with the mRNA expression of SPP1, CCL2, CD68, and MMP9. Levels of IL-1RA were not modified after modest changes in BF%, but RYGB-induced weight loss significantly decreased IL-1RA concentrations from 1233 +/- 1009 to 660 +/- 538 pg/ mL (P<0.001). Conclusion: Serum IL-1RA concentrations are increased in patients with obesity being further elevated in obesity-associated IGT and T2D in association with markers of adipose tissue dysfunction. The mRNA expression of IL1RN is markedly increased in VAT of subjects with obesity and T2D in relation with genes involved in macrophage recruitment, inflammation and matrix remodeling. Serum IL-1RA concentrations are reduced when a notable amount of BF% is loss. Measurement of IL-1RA is an excellent biomarker of adipose tissue dysfunction in obesity-associated metabolic alterations.
Autores:
Di Ciaula, A.; Bonfrate, L.; Krawczyk, M.; et al.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2022
Vol.:
23
N°:
5
Págs.:
2636
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2022
Vol.:
12
N°:
1
Págs.:
6564
Non-alcoholic fatty liver disease (NAFLD) is associated with cardiovascular disease morbimortality. However, it is not clear if NAFLD staging may help identify early or subclinical markers of cardiovascular disease. We aimed to evaluate the association of liver stiffness and serum markers of liver fibrosis with epicardial adipose tissue (EAT) and coronary artery calcium (CAC) in an observational cross-sectional study of 49 NAFLD patients that were seen at Clínica Universidad de Navarra (Spain) between 2009 and 2019. Liver elastography and non-invasive fibrosis markers were used to non-invasively measure fibrosis. EAT and CAC, measured through visual assessment, were determined by computed tomography. Liver stiffness showed a direct association with EAT (r = 0.283, p-value = 0.049) and CAC (r = 0.337, p-value = 0.018). NAFLD fibrosis score was associated with EAT (r = 0.329, p-value = 0.021) and CAC (r = 0.387, p-value = 0.006). The association of liver stiffness with CAC remained significant after adjusting for metabolic syndrome features (including carbohydrate intolerance/diabetes, hypertension, dyslipidaemia, visceral adipose tissue, and obesity). The evaluation of NAFLD severity through liver elastography or non-invasive liver fibrosis biomarkers may contribute to guide risk factor modification to reduce cardiovascular risk in asymptomatic patients. Inversely, subclinical cardiovascular disease assessment, through Visual Scale for CAC scoring, may be a simple and effective measure for patients with potential liver fibrosis, independently of the existence of other cardiovascular risk factors.
Autores:
Latorre, J.; Lluch, A.; Ortega, F. J.; et al.
Revista:
PHARMACOLOGICAL RESEARCH
ISSN:
1043-6618
Año:
2021
Vol.:
166
Págs.:
105486
Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.
Revista:
OBESITY
ISSN:
1930-7381
Año:
2021
Vol.:
29
N°:
1
Págs.:
19
As of October 2020, the Severe Acute Respiratory Syndrome coronavirus 2 (SARS¿CoV¿2), responsible for Coronavirus Disease 2019 (COVID¿19), has infected over 33million individuals and killed over one million people worldwide. (https://coronavirus.jhu.edu/map.html accessed October 1 2020) Obesity and its complications are linked to severe forms of COVID¿19, favouring an increased hospitalization and mortality rate. Despite being the gold¿standard for the treatment of selected individuals with severe obesity, there is scarce information on whether or not bariatric surgery modifies the prognosis of people living with obesity in the current COVID¿19 pandemic. Bel Lassen and colleagues have carried out the first study with a high number of patients in their sample, bringing light into this area of uncertainty. The authors provide evidence of the importance of diabetes itself as a risk factor for severe COVID¿19.
Revista:
LANCET
ISSN:
0140-6736
Año:
2021
Vol.:
397
N°:
10286
Págs.:
1687 - 1689
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2021
Vol.:
13
N°:
7
Págs.:
2128
Energy restriction is a first therapy in the treatment of obesity, but the underlying biological mechanisms have not been completely clarified. We analyzed the effects of restriction of high-fat diet (HFD) on weight loss, circulating gut hormone levels and expression of hypothalamic neuropeptides. Ten-week-old male Wistar rats (n = 40) were randomly distributed into four groups: two fed ad libitum a normal diet (ND) (N group) or a HFD (H group) and two subjected to a 25% caloric restriction of ND (NR group) or HFD (HR group) for 9 weeks. A 25% restriction of HFD over 9 weeks leads to a 36% weight loss with regard to the group fed HFD ad libitum accompanied by normal values in adiposity index and food efficiency ratio (FER). This restriction also carried the normalization of NPY, AgRP and POMC hypothalamic mRNA expression, without changes in CART. Caloric restriction did not succeed in improving glucose homeostasis but reduced HFD-induced hyperinsulinemia. In conclusion, 25% restriction of HFD reduced adiposity and improved metabolism in experimental obesity, without changes in glycemia. Restriction of the HFD triggered the normalization of hypothalamic NPY, AgRP and POMC expression, as well as ghrelin and leptin levels.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2021
Vol.:
22
N°:
16
Págs.:
8485
Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 alpha 3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.
Revista:
CELLULAR AND MOLECULAR IMMUNOLOGY
ISSN:
1672-7681
Año:
2021
Vol.:
18
N°:
10
Págs.:
2457 - 2459
Revista:
CELLULAR AND MOLECULAR IMMUNOLOGY
ISSN:
1672-7681
Año:
2021
Vol.:
18
N°:
4
Págs.:
1045 - 1057
The NLRP3-IL-1 beta pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesity-associated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case-control study. The expression of different components of the inflammasome as well as their main effectors and inflammation- and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1 beta and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-beta into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.
Autores:
Francque, S. M. (Autor de correspondencia); Marchesini, G.; Kautz, A.; et al.
Revista:
JHEP REPORTS
ISSN:
2589-5559
Año:
2021
Vol.:
3
N°:
5
Págs.:
100322
This patient guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent chronic liver disease worldwide and comes with a high disease burden. Yet, there is a lot of unawareness. Furthermore, many aspects of the disease are still to be unravelled, which has an important impact on the information that is given (or not) to patients. Its management requires a close interaction between patients and their many healthcare providers. It is important for patients to develop a full understanding of NAFLD in order to enable them to take an active role in their disease management. This guide summarises the current knowledge relevant to NAFLD and its management. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations, intended to support patients in making informed decisions.
Autores:
González-Rellán, M. J.; Fondevila, M. F.; Fernández, U.; et al.
Revista:
NATURE COMMUNICATIONS
ISSN:
2041-1723
Año:
2021
Vol.:
12
N°:
1
Págs.:
5068
p53 regulates signalling pathways involved in metabolic homeostasis. Here the authors show that O-GlcNAcylation of p53 in the liver plays a key role in the physiological regulation of glucose homeostasis, potentially via controlling the expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.
Revista:
JOURNAL OF HEPATOLOGY (ONLINE)
ISSN:
0168-8278
Año:
2021
Vol.:
74
N°:
2
Págs.:
469 - 471
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2021
Vol.:
13
N°:
4
Págs.:
1216
In children and adolescents, obesity does not seem to depend on a reduction of resting energy expenditure (REE). Moreover, in this young population, the interactions between either age and obesity or between age and gender, or the role of leptin on REE are not clearly understood. To compare the levels of REE in children and adolescents we studied 181 Caucasian individuals (62% girls) classified on the basis of age- and sex-specific body mass index (BMI) percentile as healthy weight (n = 50), with overweight (n = 34), or with obesity (n = 97) and in different age groups: 8-10 (n = 38), 11-13 (n = 50), and 14-17 years (n = 93). REE was measured by indirect calorimetry and body composition by air displacement plethysmography. Statistically significant differences in REE/fat-free mass (FFM) regarding obesity or gender were not observed. Absolute REE increases with age (p < 0.001), but REE/FFM decreases (p < 0.001) and there is an interaction between gender and age (p < 0.001) on absolute REE showing that the age-related increase is more marked in boys than in girls, in line with a higher FFM. Interestingly, the effect of obesity on absolute REE is not observed in the 8-10 year-old group, in which serum leptin concentrations correlate with the REE/FFM (r = 0.48; p = 0.011). In conclusion, REE/FFM is not affected by obesity or gender, while the effect of age on absolute REE is gender-dependent and leptin may influence the REE/FFM in 8-10 year-olds.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN:
1422-0067
Año:
2021
Vol.:
22
N°:
23
Angiopoietin-like protein 8 (ANGPTL8) is an hepatokine altered in several metabolic conditions, such as obesity, type 2 diabetes, dyslipidemia and nonalcoholic fatty liver disease (NAFLD). We sought to explore whether ANGPTL8 is involved in NAFLD amelioration after bariatric surgery in experimental models and patients with severe obesity. Plasma ANGPTL8 was measured in 170 individuals before and 6 months after bariatric surgery. Hepatic ANGPTL8 expression was evaluated in liver biopsies of patients with severe obesity undergoing bariatric surgery with available liver pathology analysis (n = 75), as well as in male Wistar rats with diet-induced obesity subjected to sham operation, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) (n = 65). The effect of ANGPTL8 on lipogenesis was assessed in human HepG2 hepatocytes under palmitate-induced lipotoxic conditions. Plasma concentrations and hepatic expression of ANGPTL8 were increased in patients with obesity-associated NAFLD in relation to the degree of hepatic steatosis. Sleeve gastrectomy and RYGB improved hepatosteatosis and reduced the hepatic ANGPTL8 expression in the preclinical model of NAFLD. Interestingly, ANGPTL8 inhibited steatosis and expression of lipogenic factors (PPARG2, SREBF1, MOGAT2 and DGAT1) in palmitate-treated human hepatocytes. Together, ANGPTL8 is involved in the resolution of NAFLD after bariatric surgery partially by the inhibition of lipogenesis in steatotic hepatocytes.
Revista:
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN:
0014-2972
Año:
2021
Vol.:
51
N°:
9
Págs.:
e13586
Revista:
JOURNAL OF INFLAMMATION RESEARCH
ISSN:
1178-7031
Año:
2021
Vol.:
14
Págs.:
6431 - 6446
Background: Inflammasomes maintain tissue homeostasis and their altered regulation in the colon, and the adipose tissue (AT) leads to chronic activation of inflammatory pathways promoting colon cancer (CC) development. We aimed to analyze the potential involvement of inflammasomes in obesity-associated CC. Methods: Ninety-nine volunteers [61 with obesity (OB) and 38 normoponderal (NP)] further subclassified according to the approved protocol for the diagnosis of CC (58 without CC and 41 with CC) were included in the case-control study. Results: CC (P<0.01) and obesity (P<0.01) were accompanied by increased mRNA levels of NLRP3, NLRP6, ASC, IL1B and NOD2 in VAT. Contrarily, patients with CC exhibited a downregulation of NLRP6 and IL18 in their colon. Additionally, we revealed that the decreased Nlrp1 (P<0.05), Nlrp3 (P<0.01) and Nlrp6 (P<0.01) mRNA levels in the colon from obese rats significantly increase (P<0.05) after caloric restriction. Adipocyteconditioned media obtained from subjects with obesity reduced (P<0.01) the mRNA of NLRP3 as well as molecules involved in maintaining the intestinal integrity (MUC2, CLDN1 and TJP1) and the anti-inflammatory factors FGF21, KLF4, and IL33 and in HT 29 cells. We also found that the knockdown of NLRP6 in HT-29 cells significantly upregulated (P<0.05) the mRNA of NLRP1 and NLRP3 and inhibited (P<0.05) the expression levels of MUC2. Finally, we showed that the incubation of HT-29 with Akkermansia muciniphila influence (P<0.05) the inflammasome expression profile as well as intestinal integrity-related genes and aberrant inflammation. Conclusions: These findings provide evidence that the downregulated levels of NLRP6 and IL18 in the colon from patients with CC may be responsible for a reduced intestinal-barrier integrity, triggering local inflammation, which in turn acts on the dysfunctional AT in obesity, increasing the expression of different inflammasome components and flaring up a vicious cycle of uncontrollable inflammatory cascades that favours a pro-tumorigenic microenvironment.
Autores:
Testa, G.; Mora-Maltas, B.; Camacho-Barcia, L.; et al.
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2021
Vol.:
13
N°:
12
Impulsive and compulsive behaviors have both been observed in individuals with obesity. The co-occurrence of obesity and type 2 diabetes (T2D) is more strongly associated with impulsivity, although there are no conclusive results yet. A multidimensional assessment of impulsivity and compulsivity was conducted in individuals with obesity in the absence or presence of T2D, compared with healthy, normal-weight individuals, with highly impulsive patients (gambling disorders), and with highly compulsive patients (anorexia nervosa). Decision making and novelty seeking were used to measure impulsivity, and cognitive flexibility and harm avoidance were used for compulsivity. For impulsivity, patients with obesity and T2D showed poorer decision-making ability compared with healthy individuals. For compulsivity, individuals with only obesity presented less cognitive flexibility and high harm avoidance; these dimensions were not associated with obesity with T2D. This study contributes to the knowledge of the mechanisms associated with diabetes and its association with impulsive-compulsive behaviors, confirming the hypothesis that patients with obesity and T2D would be characterized by higher levels of impulsivity.
Autores:
Dicker, D.; Golan, R. (Autor de correspondencia); Baker, J. L.; et al.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2021
Vol.:
14
N°:
3
Págs.:
334 - 335
Revista:
CELLS
ISSN:
2073-4409
Año:
2020
Vol.:
9
N°:
6
Págs.:
1403
Aquaporin-11 (AQP11) is expressed in human adipocytes, but its functional role remains unknown. Since AQP11 is an endoplasmic reticulum (ER)-resident protein that transports water, glycerol, and hydrogen peroxide (H2O2), we hypothesized that this superaquaporin is involved in ER stress induced by lipotoxicity and inflammation in human obesity. AQP11 expression was assessed in 67 paired visceral and subcutaneous adipose tissue samples obtained from patients with morbid obesity and normal-weight individuals. We found that obesity and obesity-associated type 2 diabetes increased (p < 0.05) AQP11 mRNA and protein in visceral adipose tissue, but not subcutaneous fat. Accordingly, AQP11 mRNA was upregulated (p < 0.05) during adipocyte differentiation and lipolysis, two biological processes altered in the obese state. Subcellular fractionation and confocal microscopy studies confirmed its presence in the ER plasma membrane of visceral adipocytes. Proinflammatory factors TNF-¿, and particularly TGF-ß1, downregulated (p < 0.05) AQP11 mRNA and protein expression and reinforced its subcellular distribution surrounding lipid droplets. Importantly, the AQP11 gene knockdown increased (p < 0.05) basal and TGF-ß1-induced expression of the ER markers ATF4 and CHOP. Together, the downregulation of AQP11 aggravates TGF-ß1-induced ER stress in visceral adipocytes. Owing to its "peroxiporin" properties, AQP11 overexpression in visceral fat might constitute a compensatory mechanism to alleviate ER stress in obesity.
Autores:
Vieira da Silva, I.; Cardoso, C.; Mendez-Gimenez, L.; et al.
Revista:
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
ISSN:
0003-9861
Año:
2020
Vol.:
691
Págs.:
108481
Aquaporins (AQPs) facilitate water and glycerol movement across membranes. AQP7 is the main aquaglyceroporin in pancreatic beta-cells and was proposed to play a role in insulin exocytosis. Although AQP7-null mice display adult-onset obesity, impaired insulin secretion and insulin resistance, AQP7 loss-of-function homozygous mutations in humans do not correlate with obesity nor type-2 diabetes. In addition, AQP12 is upregulated in pancreatitis. However, the implication of this isoform in endocrine pancreas inflammation is still unclear. Here, we investigated AQP7 and AQP12 involvement in cellular and inflammatory processes using RIN-m5F beta cells, a model widely used for their high insulin secretion. AQP7 and AQP12 expression were directly associated with cell proliferation, adhesion and migration. While tumor necrosis factor-alpha (TNF alpha)-induced inflammation impaired AQP7 expression and drastically reduced insulin secretion, lipopolysaccharides (LPS) prompted AQP7 upregulation, and both TNF alpha and LPS upregulated AQP12. Importantly, cells overexpressing AQP12 are more resistant to inflammation, revealing lower levels of proinflammatory markers. Altogether, these data document AQP7 involvement in insulin secretion and AQP12 implication in inflammation, highlighting their fundamental role in pancreatic beta-cell function.
Autores:
Fernandez-Aranda, F. (Autor de correspondencia); Munguia, L. ; Mestre-Bach, G. ; et al.
Revista:
EUROPEAN EATING DISORDERS REVIEW
ISSN:
1072-4133
Año:
2020
Vol.:
28
N°:
6
Págs.:
871 - 883
Confinement during the COVID-19 pandemic is expected to have a serious and complex impact on the mental health of patients with an eating disorder (ED) and of patients with obesity. The present manuscript has the following aims: (1) to analyse the psychometric properties of the COVID Isolation Eating Scale (CIES), (2) to explore changes that occurred due to confinement in eating symptomatology; and (3) to explore the general acceptation of the use of telemedicine during confinement. The sample comprised 121 participants (87 ED patients and 34 patients with obesity) recruited from six different centres. Confirmatory Factor Analyses (CFA) tested the rational-theoretical structure of the CIES. Adequate goodness-of-fit was obtained for the confirmatory factor analysis, and Cronbach alpha values ranged from good to excellent. Regarding the effects of confinement, positive and negative impacts of the confinement depends of the eating disorder subtype. Patients with anorexia nervosa (AN) and with obesity endorsed a positive response to treatment during confinement, no significant changes were found in bulimia nervosa (BN) patients, whereas Other Specified Feeding or Eating Disorder (OSFED) patients endorsed an increase in eating symptomatology and in psychopathology. Furthermore, AN patients expressed the greatest dissatisfaction and accommodation difficulty with remote therapy when compared with the previously provided face-to-face therapy. The present study provides empirical evidence on the psychometric robustness of the CIES tool and shows that a negative confinement impact was associated with ED subtype, whereas OSFED patients showed the highest impairment in eating symptomatology and in psychopathology.
Revista:
JOURNAL OF CLINICAL MEDICINE
ISSN:
2077-0383
Año:
2020
Vol.:
9
N°:
4
Págs.:
1069
Compelling evidence suggests that dermatopontin (DPT) regulates collagen and fibronectin fibril formation, the induction of cell adhesion and the prompting of wound healing. We aimed to evaluate the role of DPT on obesity and its associated metabolic alterations as well as its impact in visceral adipose tissue (VAT) inflammation and extracellular matrix (ECM) remodelling. Samples obtained from 54 subjects were used in a case-control study. Circulating and VAT expression levels of DPT as well as key ECM remodelling- and inflammation-related genes were analysed. The effect of pro- and anti-inflammatory mediators on the transcript levels of DPT in visceral adipocytes was explored. The impact of DPT on ECM remodelling and inflammation pathways was also evaluated in cultured adipocytes. We show that obesity and obesity-associated type 2 diabetes (T2D) increased (p < 0.05) circulating levels of DPT. In this line, DPT mRNA in VAT was increased (p < 0.05) in obese patients with and without T2D. Gene expression levels of DPT were enhanced (p < 0.05) in human visceral adipocytes after the treatment with lipopolysaccharide, tumour growth factor (TGF)-beta and palmitic acid, whereas a downregulation (p < 0.05) was detected after the stimulation with interleukin (IL)-4 and IL-13, critical cytokines mediating anti-inflammatory pathways. Additionally, we revealed that DPT increased (p < 0.05) the expression of ECM- (COL6A3, ELN, MMP9, TNMD) and inflammation-related factors (IL6, IL8, TNF) in human visceral adipocytes. These findings provide, for the first time, evidence of a novel role of DPT in obesity and its associated comorbidities by influencing AT remodelling and inflammation.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2020
Vol.:
13
N°:
2
Págs.:
292 - 296
Revista:
JOURNAL OF HEADACHE AND PAIN
ISSN:
1129-2369
Año:
2020
Vol.:
21
N°:
1
Págs.:
9
Objective To investigate the specific relationship between cutaneous allodynia (CA) and the percentages of body fat (BF) and abdominal fat in migraineurs. Additionally, we compared serum levels of inflammatory biomarkers in patients with and without CA. Background Excess abdominal fat might facilitate progressive changes in nociceptive thresholds causing central sensitization, clinically reflected as CA, which could drive migraine progression. Methods This prospective cohort study included 80 patients with migraine (mean age 39 years, 81.2% female) and 39 non-migraine controls. We analysed each participant's height, body weight, and body mass index (BMI). The amount and distribution of BF was also assessed by air displacement plethysmography (ADP) and ViScan, respectively. We analysed serum levels of markers of inflammation, during interictal periods. Results We studied 52 patients with episodic migraine (EM) and 28 with chronic migraine (CM). Of the 80 patients, 53 (53.8%) had CA. Migraineurs with CA had a higher proportion of abdominal fat values than patients without CA (p = 0.04). The independent risk factors for CA were the use of migraine prophylaxis (OR 3.26, 95% CI [1.14 to 9.32]; p = 0.03), proportion of abdominal fat (OR 1.13, 95% CI [1.01 to 1.27]; p = 0.04), and presence of sleep disorders (OR 1.13, 95% CI [00.01 to 1.27]; p = 0.04). The concordance correlation coefficient between the ADP and BMI measurements was 0.51 (0.3681 to 0.6247). CA was not correlated with the mean plasma levels of inflammatory biomarkers. Conclusions There is a relation between excess abdominal fat and CA. Abdominal obesity might contribute to the development of central sensitization in migraineurs, leading to migraine chronification.
Autores:
Frühbeck, Gema; Fernandez-Quintana, B. ; Paniagua, M.; et al.
Revista:
METABOLISM-CLINICAL AND EXPERIMENTAL
ISSN:
0026-0495
Año:
2020
Vol.:
108
Págs.:
154261
Background: Fibronectin type IIIdomain-containing protein 4 (FNDC4) constitutes a secreted factor showing a high homology in the fibronectin type III and transmembrane domains with the exercise-associated myokine irisin (FNDC5). We sought to evaluate whether FNDC4 mimics the anti-obesity effects of FNDC5/irisin in human adipose tissue.
Methods: Plasma and adipose tissue samples of 78 patients with morbid obesity undergoing bariatric surgery and 26 normal-weight individuals were used in the present study.
Results: Plasma FNDC4 was decreased in patients with morbid obesity, related to obesity-associated systemic inflammation and remained unchanged six months after bariatric surgery. Visceral adipose tissue from patients with morbid obesity showed higher expression of FNDC4 and its putative receptor GPR116 regardless of the degree of insulin resistance. FNDC4 content was regulated by lipogenic, lipolytic and proinflammatory stimuli in human visceral adipocytes. FNDC4 reduced intracytosolic lipid accumulation and stimulated a brown-like pattern in human adipocytes, as evidenced by an upregulated expression of UCP-1 and the brown/beige adipocyte markers PRDM16, TMEM26 and CD137. Moreover, FNDC4 treatment upregulated mitochondrial DNA content and factors involved in mitochondrial biogenesis (TFAM, NRF1 and NRF2). Human FNDC4-knockdown adipocytes exhibited an increase in lipogenesis and a reduction of brown/beige-specific fat markers as well as factors involved in mitochondrial biogenesis.
Conclusions: Taken together, the novel adipokine FNDC4 reduces lipogenesis and increases fat browning in human visceral adipocytes. The upregulation of FNDC4 in human visceral fat might constitute an attempt to attenuate the adipocyte hypertrophy, inflammation and impaired beige adipogenesis in the obese state.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2020
Vol.:
30
N°:
11
Págs.:
4293 - 4299
Background Weight loss after bariatric surgery varies among patients. Patients who do not complete long-term follow-up are considered to loose less weight than those with regular follow-up visits. Objective To evaluate the influence of patients' follow-up compliance on long-term excess weight loss (%EWL) and total weight loss (%TWL) after bariatric surgery, comparing results between gastric bypass (GB) and sleeve gastrectomy (SG). Methods Patients with up to 5 years of follow-up data after bariatric surgery were included in this retrospective analysis. Patients were divided in 2 groups: those in group 1 who had attended every scheduled postoperative appointment and those in group 2 who had been lost to follow-up before 1 year and were later contacted by telephone. %EWL and %TWL were compared to determine the possible relationship between type of surgery and regularity of the follow-up. Results A total of 385 patients were included. A significant difference in EWL was observed at 5 years in the SG group (78% for group 1 versus 39% for group 2;p = 0.02) and GB group (75% for group 1 versus 62% for group 2;p = 0.01). No significant differences between surgeries were found when comparing long-term EWL in group 1 patients 77% for SG versus 75% for GB. For group 2 patients, GB achieved greater EWL than SG;p = 0.005. %TWL patients in group 2 showed significant differences in all periods of study (p < 0.05). Conclusion Bariatric surgery patients who attended all scheduled follow-up appointments experienced significantly greater long-term EWL and TWL than those who did not. GB has apparent increased benefits for weight loss in long-term follow-up when compared with SG for patients who did not attend long-term follow-up. Therefore, continued long-term follow-up of bariatric patients should be encouraged to increase postoperative weight loss results.
Autores:
Weber, M. ; Mera, P.; Casas, J. ; et al.
Revista:
FASEB JOURNAL
ISSN:
0892-6638
Año:
2020
Vol.:
34
N°:
9
Págs.:
11816 - 11837
The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.
Autores:
Alligier, M. ; Barres, R. ; Blaak, E. E.; et al.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2020
Vol.:
13
N°:
1
Págs.:
1 - 28
Heterogeneity of interindividual and intraindividual responses to interventions is often observed in randomized, controlled trials for obesity. To address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. This project, called OBEDIS (OBEsity Diverse Interventions Sharing - focusing on dietary and other interventions), provides a set of European guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. Broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. In this way, studies across Europe may be pooled for better prediction of individuals' responses to an intervention for obesity - ultimately leading to better patient care and improved obesity outcomes.
Autores:
Goossens, G. H. (Autor de correspondencia); Dicker, D. ; Farpour-Lambert, N. J.; et al.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2020
Vol.:
13
N°:
4
Págs.:
439 - 452
Accumulating evidence suggests that obesity is a major risk factor for the initiation, progression, and outcomes of coronavirus disease 2019 (COVID-19). The European Association for the Study of Obesity (EASO), as a scientific and medical society dedicated to the promotion of health and well-being, is greatly concerned about the concomitant obesity and COVID-19 pandemics and their impact on health and society at large. In this perspective, we will address the inherent immunological perturbations and alterations in the renin-angiotensin-aldosterone system in patients with obesity and COVID-19, and discuss how these impairments may underlie the increased susceptibility and more detrimental outcomes of COVID-19 in people with obesity. Clearly, this has important implications for preventive measures, vaccination, and future therapeutic strategies to combat COVID-19. Furthermore, we will highlight important knowledge gaps and provide suggestions for future research and recommendations for policy actions. Since many new reports on COVID-19 rapidly appear, the present perspective should be seen as a focus for discussion to drive forward further understanding, research initiatives, and clinical management of COVID-19.
Autores:
Dicker, D. (Autor de correspondencia); Bettini, S.; Farpour-Lambert, N. ; et al.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2020
Vol.:
13
N°:
4
Págs.:
430 - 438
The World Health Organization declared COVID-19, the infectious disease caused by the coronavirus SARS-CoV-2, a pandemic on March 12, 2020. COVID-19 is causing massive health problems and economic suffering around the world. The European Association for the Study of Obesity (EASO) promptly recognised the impact that the outbreak could have on people with obesity. On one side, emerging data suggest that obesity represents a risk factor for a more serious and complicated course of COVID-19 in adults. On the other side, the health emergency caused by the outbreak diverts attention from the prevention and care of non-communicable chronic diseases to communicable diseases. This might be particularly true for obesity, a chronic and relapsing disease frequently neglected and linked to significant bias and stigmatization. The Obesity Management Task Force (OMTF) of EASO contributes in this paper to highlighting the key aspects of these two sides of the coin and suggests some specific actions.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2020
Vol.:
44
N°:
2
Págs.:
475 - 487
BACKGROUND/OBJECTIVES:
Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB).
SUBJECTS/METHODS:
Plasma ghrelin isoforms were measured in male Wistar rats (n¿=¿129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed.
RESULTS:
Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68+- and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2¿. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1¿, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78.
CONCLUSIONS:
Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.
Revista:
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN:
0014-2972
Año:
2020
Vol.:
50
N°:
11
Págs.:
e13307
Background: Obesity is a major public health problem, which continues to be diagnosed and classified by BMI, excluding the most elemental concepts of the precision medicine approach. Obesity does not equally affect males and females, even with the same BMI. Microalbuminuria is a risk marker of cardiovascular disease closely related to obesity. The aim of this study was to evaluate the gender-dependent differences in the development of early obesity-related disease, focusing on pathologic microalbuminuria (PMA).
Material and methods: We developed a single-centre cross-sectional study including 1068 consecutive adults from May 2016 to January 2018, divided into two groups: one including the first 787 patients attended, evaluated as a description population; the second group included 281 subjects analysed as an external validation population. Collected data included medical history, anthropometric measures, abdominal bioimpedance and routine laboratory tests.
Results: First, we confirmed the lack of accuracy of classic obesity measures in predicting microalbuminuria. Second, we tested the utility of a tailored evaluation to predict PMA, with an area under the ROC curve of 0.78 for females and 0.82 for males. We also confirmed the different physiology of visceral adiposity for males when compared to females, in which small variations of fat mass entail major changes in the clinical repercussion. Third, we performed an external validation of our results, achieving a 77% accuracy rate.
Conclusions: Our findings support that there is an individual threshold of fat amount necessary to develop obesity-dependent PMA and that gender plays a major role in the interplay between PMA and adiposity.
Revista:
LANCET DIABETES AND ENDOCRINOLOGY
ISSN:
2213-8587
Año:
2019
Vol.:
7
N°:
10
Págs.:
743 - 745
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2019
Vol.:
11
N°:
2
Págs.:
E454
Obesity favors the development of cardiometabolic alterations such as type 2 diabetes (T2D) and the metabolic syndrome (MS). Obesity and the MS are distinguished by an increase in circulating leptin concentrations, in parallel to a drop in the levels of adiponectin. Consequently, the Adpn/Lep ratio has been suggested as a maker of dysfunctional adipose tissue. We aimed to investigate in humans (n = 292) the reliability of the Adpn/Lep ratio as a biomarker of adipose tissue dysfunction. We considered that an Adpn/Lep ratio of ¿1.0 can be considered normal, a ratio of ¿0.5 <1.0 suggests moderate-medium increased risk, and a ratio of <0.5 indicates a severe increase in cardiometabolic risk. Using these cut-offs, 5%, 54% and 48% of the lean, normoglycemic and without-MS subjects, respectively, fall within the group with an Adpn/Lep ratio below 0.5; while 89%, 86% and 90% of the obese, with T2D and with MS patients fall within the same group (p < 0.001). A significant negative correlation (r = -0.21, p = 0.005) between the Adpn/Lep ratio and serum amyloid A (SAA) concentrations, a marker of adipose tissue dysfunction, was found. We concluded that the Adpn/Lep ratio is a good indicator of a dysfunctional adipose tissue that may be a useful estimator of obesity- and MS-associated cardiometabolic risk, allowing the identification of a higher number of subjects at risk.
Revista:
AGING-US
ISSN:
1945-4589
Año:
2019
Vol.:
11
N°:
6
Págs.:
1733 - 1744
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta (TGF beta) superfamily which declines with age and exerts anti-aging regenerative effects in skeletal muscle in mice. However, recent data in humans and mice are conflicting casting doubts about its true functional actions. The aim of the present study was to compare the circulating concentrations of GDF11 in individuals of different ages as well as body weight and glycemic status. Serum concentrations of GDF11 were measured by ELISA in 319 subjects. There was a significant increase in GDF11 concentrations in people in the 41-50 y group and a decline in the elder groups (61-70 and 71-80 y groups, P=0.008 for the comparison between all age groups). However, no significant correlation between fat-free mass index (FFMI), a formula used to estimate the amount of muscle mass in relation to height, and IogGDF11 was observed (r=0.08, P=0.197). Moreover, no significant differences in circulating concentrations of GDF11 regarding obesity or glycemic status were found. Serum GDF11 concentrations in humans decrease in older ages being unaltered in obesity and T2D. Further studies should determine the exact pathophysiological role of GDF11 in aging.
Revista:
JOURNAL OF CLINICAL MEDICINE
ISSN:
2077-0383
Año:
2019
Vol.:
8
N°:
6
Págs.:
878
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor (TGF)-beta superfamily which declines with age and has been proposed as an anti-aging factor with regenerative effects in skeletal muscle in mice. However, recent data in humans and mice are conflicting, casting doubts about its true functional actions. The aim of the present study was to analyze the potential involvement of GFD11 in energy homeostasis in particular in relation with thyroid hormones. Serum concentrations of GDF11 were measured by enzyme-linked immunosorbent assay (ELISA) in 287 subjects. A highly significant positive correlation was found between GDF11 and thyroid-stimulating hormone (TSH) concentrations (r = 0.40, p < 0.001). Neither resting energy expenditure (REE) nor REE per unit of fat-free mass (REE/FFM) were significantly correlated (p > 0.05 for both) with GDF11 levels. In a multiple linear regression analysis, the model that best predicted logGDF11 included logTSH, leptin, body mass index (BMI), age, and C-reactive protein (logCRP). This model explained 37% of the total variability of logGDF11 concentrations (p < 0.001), with only logTSH being a significant predictor of logGDF11. After segregating subjects by TSH levels, those within the low TSH group exhibited significantly decreased (p < 0.05) GDF11 concentrations as compared to the normal TSH group or the high TSH group. A significant correlation of GDF11 levels with logCRP (r = 0.19, p = 0.025) was found. GDF11 levels were not related to the presence of hypertension or cardiopathy. In conclusion, our results show that circulating concentrations of GDF11 are closely associated with TSH concentrations and reduced in subjects with low TSH levels. However, GDF11 is not related to the regulation of energy expenditure. Our data also suggest that GDF11 may be involved in the regulation of inflammation, without relation to cardiac function. Further research is needed to elucidate the role of GDF11 in metabolism and its potential involvement in thyroid pathophysiology.
Autores:
Ortega, F. J. (Autor de correspondencia); Moreno-Navarrete, J. M.; Mercader, J. M.; et al.
Revista:
FASEB JOURNAL
ISSN:
0892-6638
Año:
2019
Vol.:
33
N°:
8
Págs.:
9656 - 9671
During adipogenesis, preadipocytes' cytoskeleton reorganizes in parallel with lipid accumulation. Failure to do so may impact the ability of adipose tissue (AT) to shift between lipid storage and mobilization. Here, we identify cytoskeletal transgelin 2 (TAGLN2) as a protein expressed in AT and associated with obesity and inflammation, being normalized upon weight loss. TAGLN2 was primarily found in the adipose stromovascular cell fraction, but inflammation, TGF-beta, and estradiol also prompted increased expression in human adipocytes. Tagln2 knockdown revealed a key functional role, being required for proliferation and differentiation of fat cells, whereas transgenic mice overexpressing Tagln2 using the adipocyte protein 2 promoter disclosed remarkable sex-dependent variations, in which females displayed healthy obesity and hypertrophied adipocytes but preserved insulin sensitivity, and males exhibited physiologic changes suggestive of defective AT expandability, including increased number of small adipocytes, activation of immune cells, mitochondrial dysfunction, and impaired metabolism together with decreased insulin sensitivity. The metabolic relevance and sexual dimorphism of TAGLN2 was also outlined by genetic variants that may modulate its expression and are associated with obesity and the risk of ischemic heart disease in men. Collectively, current findings highlight the contribution of cytoskeletal TAGLN2 to the obese phenotype in a gender-dependent manner.-Ortega, F. J., Moreno-Navarrete, J. M., Mercader, J. M., Gomez-Serrano, M., Garcia-Santos, E., Latorre, J., Lluch, A., Sabater, M., Caballano-Infantes, E., Guzman, R., Macias-Gonzalez, M., Buxo, M., Girones, J., Vilallonga, R., Naon, D., Botas, P., Delgado, E., Corella, D., Burcelin, R., Fruhbeck, G., Ricart, W., Simo, R., Castrillon-Rodriguez, I., Tinahones, F. J., Bosch, F., Vidal-Puig, A., Malagon, M. M., Peral, B., Zorzano, A., Fernandez-Real, J. M. Cytoskeletal transgelin 2 contributes to gender-dependent adipose tissue expandability and immune function.
Revista:
JOURNAL OF TRANSLATIONAL MEDICINE
ISSN:
1479-5876
Año:
2019
Vol.:
17
Págs.:
48
Background and aims: Obesity is associated with impaired glucose tolerance which is a risk factor for cardiovascular risk. However, the oral glucose tolerance test (OGTT) is not usually performed in patients with normal fasting glycaemia, thus offering false reassurance to patients with overweight or obesity who may have post-prandial hyperglycaemia. As an alternative to resource demanding OGTTs, we aimed to examine the predictive value of anthropometric measures of total and central fat distribution for post-prandial hyperglycaemia in patients with overweight and obesity with normal fasting glycaemia enrolled in the DICAMANO study. Methods: We studied 447 subjects with overweight/obesity with a fasting glucose value <= 5.5 mmol l(-1) (99 mg dl(-1)) and BMI >= 25 kg/m(2) who underwent a 75-g OGTT. Post-prandial hyperglycaemia was defined as a glucose level >= 7.8 mmol l(-1) (140 mg dl(-1)) 2-h after the OGTT. The anthropometric measurements included body mass index, body adiposity index, waist circumference, neck circumference, waist-to-hip ratio and waist-to-height ratio. Results: The prevalence of post-prandial hyperglycaemia was 26%. Mean 1-h OGTT glucose levels, insulin resistance and beta cell dysfunction was higher in those subjects in the highest tertile for each anthropometric measurement, irrespective of fasting glucose level. Central fat depot anthropometric measurements were strongly and independently associated with an increased risk of post-prandial hyperglycaemia. After multivariable-adjustment for fasting plasma glucose level, smoking, and physical activity level, the odds ratio (95% confidence intervals) for the presence of post-prandial hyperglycaemia for neck circumference, waist circumference and waist-to-height ratio were 3.3 (1.4, 7.7), 2.4 (1.4, 4.4) and 2.5 (1.4, 4.5), respectively. Conclusions: In this large and comprehensively phenotyped cohort, one in four subjects had post-prandial hyperglycaemia despite normal fasting glycaemia. Anthropometric indices of central fat distribution were strongly and independently associated with an increased risk of post-prandial hyperglycaemia. These results support the association between central adiposity and glucose derangements and demonstrate the clinical usefulness of anthropometric measurements as screening tools for the selection of patients who are most likely to benefit from an OGTT.
Revista:
JOURNAL OF CLINICAL MEDICINE
ISSN:
2077-0383
Año:
2019
Vol.:
8
N°:
4
Págs.:
479
Objective: Glucagon-like peptide (GLP)-1 has been proposed as a key candidate in glucose improvements after bariatric surgery. Our aim was to explore the role of GLP-1 in surgically-induced type 2 diabetes (T2D) improvement and its capacity to regulate human adipocyte inflammation. Methods: Basal circulating concentrations of GLP-1 as well as during an oral glucose tolerance test (OGTT) were measured in lean and obese volunteers with and without T2D (n = 93). In addition, GLP-1 levels were determined before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 77). The impact of GLP-1 on inflammation signalling pathways was also evaluated. Results: We show that the reduced (p < 0.05) circulating levels of GLP-1 in obese T2D patients increased (p < 0.05) after RYGB. The area under the curve was significantly lower in obese patients with (p < 0.01) and without (p < 0.05) T2D compared to lean volunteers while obese patients with T2D exhibited decreased GLP-1 levels at baseline (p < 0.05) and 120 min (p < 0.01) after the OGTT. Importantly, higher (p < 0.05) pre-operative GLP-1 concentrations were found in patients with T2D remission after RYGB. We also revealed that exendin-4, a GLP-1 agonist, downregulated the expression of inflammation-related genes (IL1B, IL6, IL8, TNF) and, conversely, upregulated the mRNA levels of ADIPOQ in human visceral adipocytes. Furthermore, exendin-4 blocked (p < 0.05) LPS-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Conclusions: Our data indicate that GLP-1 may contribute to glycemic control and exert a role in T2D remission after RYGB. GLP-1 is also involved in limiting inflammation in human visceral adipocytes.
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2019
Vol.:
104
N°:
1
Págs.:
21 - 37
CONTEXT:
Human obesity is associated with increased circulating TNF-¿, a proinflammatory cytokine that induces hepatocyte cell death.
OBJECTIVE:
The potential beneficial effects of acylated and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-¿-induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated.
DESIGN, SETTINGS, AND PARTICIPANTS:
Plasma ghrelin isoforms and TNF-¿ were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-¿-induced cell death was determined in vitro in human HepG2 hepatocytes.
RESULTS:
Circulating TNF-¿ and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-¿-induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-¿-activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR.
CONCLUSIONS:
Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-¿-induced hepatocyte apoptosis, autophagy, and pyroptosis.
Autores:
Folgueira, C.; Beiroa, D.; Porteiro, B. ; et al.
Revista:
NATURE METABOLISM
ISSN:
2522-5812
Año:
2019
Vol.:
1
N°:
8
Págs.:
811 - 829
Dopamine signalling is a crucial part of the brain reward system and can affect feeding behaviour. Dopamine receptors are also expressed in the hypothalamus, which is known to control energy metabolism in peripheral tissues. Here we show that pharmacological or chemogenetic stimulation of dopamine receptor 2 (D2R) expressing cells in the lateral hypothalamic area (LHA) and the zona incerta (ZI) decreases body weight and stimulates brown fat activity in rodents in a feeding-independent manner. LHA/ZI D2R stimulation requires an intact sympathetic nervous system and orexin system to exert its action and involves inhibition of PI3K in the LHA/ZI. We further demonstrate that, as early as 3 months after the onset of treatment, patients treated with the D2R agonist cabergoline experience an increase in energy expenditure that persists for one year, leading to total body weight and fat loss through a prolactin-independent mechanism. Our results may provide a mechanistic explanation for how clinically used D2R agonists act in the central nervous system to regulate energy balance.
Revista:
NUTRIENTS
ISSN:
2072-6643
Año:
2019
Vol.:
11
N°:
9
Págs.:
2069
Bariatric surgery remains the most effective option for achieving important and sustained weight loss. We explored the effects of Roux-en-Y gastric bypass (RYGB) on the circulating levels of adiponectin, leptin, and the adiponectin/leptin (Adpn/Lep) ratio in patients with obesity and type 2 diabetes (T2D). Twenty-five T2D volunteers undergoing RYGB were included in the study, and further subclassified as patients that responded or not to RYBG, regarding remission of T2D. Anthropometric and biochemical variables were evaluated before and after RYGB. Obese patients with T2D exhibited an increase (p < 0.0001) in the Adpn/Lep ratio after RYGB. Changes in the Adpn/Lep ratio correlated better with changes in anthropometric data (p < 0.001) than with the variations of adiponectin or leptin alone. Multiple regression analysis revealed that the change in the Adpn/Lep ratio in patients with T2D was an independent predictor of the changes in body mass index (p < 0.001) and body fat percentage (p = 0.022). However, the Adpn/Lep ratio did not differ between individuals with or without T2D remission after RYGB. In summary, the current study demonstrated that after weight and body fat loss following RYGB, the Adpn/Lep ratio increased in patients with obesity and T2D.
Revista:
EXPERT OPINION ON PHARMACOTHERAPY
ISSN:
1465-6566
Año:
2019
Vol.:
20
N°:
4
Págs.:
367 - 371
Autores:
Steward, T. ; Mestre-Bach, G.; Granero, R. ; et al.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2019
Vol.:
9
N°:
1
Págs.:
7910
Orexins/hypocretins are neuropeptides implicated in numerous processes, including food intake and cognition. The role of these peptides in the psychopathology of anorexia nervosa (AN) remains poorly understood. The aim of the current study was to evaluate the associations between plasma orexin-A (OXA) concentrations and neuropsychological functioning in adult women with AN, and a matched control group. Fasting plasma OXA concentrations were taken in 51 females with AN and in 51 matched healthy controls. Set-shifting was assessed using the Wisconsin Card Sorting Test (WCST), whereas decision making was measured using the Iowa Gambling Task (IGT). The AN group exhibited lower plasma OXA levels than the HC group. Lower mean scores were obtained on the IGT in AN patients. WCST perseverative errors were significantly higher in the AN group compared to HC. In both the AN and HC group, OXA levels were negatively correlated with WCST non-perseverative errors. Reduced plasma OXA concentrations were found to be associated with set-shifting impairments in AN. Taking into consideration the function of orexins in promoting arousal and cognitive flexibility, future studies should explore whether orexin partly underpins the cognitive impairments found in AN.
Autores:
Christou, G. A. ; Katsiki, N.; Blundell, J. ; et al.
Revista:
OBESITY REVIEWS
ISSN:
1467-7881
Año:
2019
Vol.:
20
N°:
6
Págs.:
805 - 815
Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a long elimination half-life, allowing subcutaneous (sc) administration once per week. Both the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) recently approved once-weekly sc semaglutide for the treatment of type 2 diabetes mellitus (T2DM). The weight loss efficacy of once-weekly sc semaglutide appears to be superior compared with the other once-weekly GLP-1 RAs in patients with T2DM. Semaglutide was recently evaluated as an antiobesity drug in a phase II dose-finding trial, which demonstrated superior weight loss efficacy of once daily sc semaglutide compared with both placebo and once daily 3.0 mg liraglutide in patients with obesity but without T2DM. The magnitude of semaglutide-induced weight loss in this study exceeded the criteria of both the EMA and FDA for antiobesity drugs, and there were no safety concerns, indicating the eligibility of once daily sc semaglutide as a future antiobesity drug.
Autores:
Grattagliano, I. ; Montezinho, L. P.; Oliveira, P. J.; et al.
Revista:
BIOCHEMICAL PHARMACOLOGY
ISSN:
0006-2952
Año:
2019
Vol.:
160
Págs.:
34 - 45
Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by the excessive accumulation of triglycerides in hepatocytes. NAFLD is the most frequent chronic liver disease in developed countries, and is often associated with metabolic disorders such as obesity and type 2 diabetes. NAFLD definition encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL), to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD, therefore, represents a global public health issue. Mitochondrial dysfunction occurs in NAFLD, and contributes to the progression to the necro-inflammatory and fibrotic form (NASH). Disrupted mitochondrial function is associated with a decrease in the energy levels and impaired redox balance, and negatively affects cell survival by altering overall metabolism and subcellular trafficking. Such events reduce the tolerance of hepatocytes towards damaging hits, and favour the injurious effects of extra-cellular factors. Here, we discuss the role of mitochondria in NAFLD and focus on potential therapeutic approaches aimed at preserving mitochondrial function.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2019
Vol.:
12
N°:
2
Págs.:
131 - 136
Obesity is a frequent, serious, complex, relapsing, and chronic disease process that represents a major public health problem. The coining of obesity as an adiposity-based chronic disease (ABCD) is of particular relevance being in line with EASO's proposal to improve the International Classification of Diseases ICD-11 diagnostic criteria for obesity based on three dimensions, namely etiology, degree of adiposity, and health risks. The body mass index as a unique measurement of obesity does not reflect the whole complexity of the disease. Obesity complications are mainly determined by 2 pathological processes, i.e., physical forces (fat mass disease) as well as endocrine and immune responses (sick fat disease), which are embedded in a cultural and physical context leading to a specific ABCD stage. (c) 2019 The Author(s) Published by S. Karger AG, Basel
Revista:
REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
ISSN:
1130-0108
Año:
2019
Vol.:
111
N°:
5
Págs.:
371 - 377
Purpose: to assess the long-term benefits of bariatric surgery in super-obese (body mass index [BMI] = 50) and in elderly obese (age > 60 years) populations.
Methods: one hundred and twenty one patients who underwent laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy in a university hospital were retrospectively subdivided into the following groups: BMI < 50 vs = 50 and age < 60 vs = 60 years. Weight loss, body composition and comorbidity outcomes were registered after one and six months and one, two, three and five years with 100%, 93%, 89%, 80%, 75% and 60% successful follow-up.
Results: the percentage of excess BMI loss (% EBMIL) was comparable between BMI groups and age groups and the difference in the long-term follow up was not statistically significant (p > 0.05). Complication rates, comorbidity resolution, reduction in body fat and increase in fat-free mass were comparable between BMI groups and age groups. Gastric bypass resulted in a greater weight loss compared to sleeve gastrectomy. The % EBMIL was 65.2% vs 46.7% (p = 0.002), 65.8% vs 44.9% (p = 0.004), 64.4% vs 30.5% (p = 0.001), 55.6% vs 17.6% (p = 0.016) at one, two, three and five years postoperative, respectively. Similarly, in the super-obese group, weight loss was more pronounced after gastric bypass versus sleeve gastrectomy.
Conclusions: bariatric surgery in super-obese and elderly populations is an effective and safe weight loss measure with a good comorbidity resolution in the long-term. Gastric bypass is superior to sleeve gastrectomy in terms of long-term weight loss and comorbidity resolution in all the groups investigated.
Revista:
GENES
ISSN:
2073-4425
Año:
2019
Vol.:
10
N°:
3
Págs.:
184
The role of extracellular matrix (ECM) remodeling in fibrosis progression in nonalcoholic fatty liver disease (NAFLD) is complex and dynamic, involving the synthesis and degradation of different ECM components, including tenascin C (TNC). The aim was to analyze the influence of inducible nitric oxide synthase (iNOS) deletion on inflammation and ECM remodeling in the liver of ob/ob mice, since a functional relationship between leptin and iNOS has been described. The expression of molecules involved in inflammation and ECM remodeling was analyzed in the liver of double knockout (DBKO) mice simultaneously lacking the ob and the iNOS genes. Moreover, the effect of leptin was studied in the livers of ob/ob mice and compared to wild-type rodents. Liver inflammation and fibrosis were increased in leptin-deficient mice. As expected, leptin treatment reverted the obesity phenotype. iNOS deletion in ob/ob mice improved insulin sensitivity, inflammation, and fibrogenesis, as evidenced by lower macrophage infiltration and collagen deposition as well as downregulation of the proinflammatory and profibrogenic genes including Tnc. Circulating TNC levels were also decreased. Furthermore, leptin upregulated TNC expression and release via NO-dependent mechanisms in AML12 hepatic cells. iNOS deficiency in ob/ob mice improved liver inflammation and ECM remodeling-related genes, decreasing fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in hepatocytes, suggesting an important role of this alarmin in the development of NAFLD.
Revista:
ADIPOCYTE
ISSN:
2162-3945
Año:
2018
Vol.:
7
N°:
1
Págs.:
57 - 62
Obesity is currently the most extended metabolic disturbance worldwide favoring the development of cardiometabolic alterations such as type 2 diabetes, hypertension, and dyslipidemia. Obesity and the metabolic syndrome (MS) are characterized by an increase in circulating leptin concentrations, in parallel to a decrease in blood levels of adiponectin. Consequently, the adiponectin/leptin ratio has been suggested as a maker of adipose tissue dysfunction. This emerging biomarker correlates with insulin resistance better than adiponectin or leptin alone, or even HOMA and is decreased with increasing number of metabolic risk factors having been proposed as a predictive marker for the MS. Moreover, the adiponectin/leptin ratio is negatively correlated with markers of low-grade chronic inflammation. In this sense, an increase in this ratio has been related with reduced atherosclerosis risk as well as with a decreased risk of some types of cancer in epidemiological studies. In this commentary we propose new cutoffs to estimate obesity- and MS-associated cardiometabolic risk according to the adiponectin/leptin ratio and discuss different therapeutic strategies to increase this promising biomarker of metabolic risk.
Revista:
LANCET DIABETES AND ENDOCRINOLOGY
ISSN:
2213-8587
Año:
2018
Vol.:
6
N°:
3
Págs.:
161 - 163
Revista:
CLINICAL NUTRITION
ISSN:
0261-5614
Año:
2018
Vol.:
37
N°:
2
Págs.:
580 - 589
Background & aims: Visceral adipose tissue (VAT) has been shown to be profoundly responsible of most of the obesity-associated metabolic derangements. The measurement of VAT usually implies the use of imaging techniques such as magnetic resonance imaging or computed tomographi(CT), Our aim was to evaluate the accuracy of the determination of VAT by means of abdominal bioimpedance (BIA) with the ViScan device in comparison with Cr and its clinical usefulness in the management of obesity. Methods: We studied a sample of 140 subjects (73 males/67 females) with BMI ranging from 17.7 to 50.4 kg/m(2) to evaluate the accuracy of the ViScan in comparison to CT to determine VAT. To further analyze ViScan's clinical usefulness we studied a separate cohort (n = 2849) analyzing cardiometabolic risk factors. Furthermore, we studied the ability of the ViScan to detect changes in VAT after weight gain (n = 107) or weight loss (n = 335). The study was performed from October 2009 through June 2015. Results: ViScan determines VAT with a good accuracy in individuals with a CT-VAT up to 200 cm(2), and then with lower precision with increasing body mass, exhibiting a moderate high correlation with Cri VAT (r = 0.75, P < 0.001). Importantly, VAT determination with the ViScan exhibits better correlations with several cardiometabolic risk factors such as glucose, triglycerides, HDL-cholesterol and markers of fatty liver than anthropometric measurements such as BMI or waist circumference. ViScan is able to detect VAT variations after body weight changes. Conclusions: Since the possibility of measuring VAT by imaging techniques is not always available, abdominal BIA represents a good alternative to estimate VAT, allowing the identification of patients with increased VAT-related cardiometabolic risk and a better management of obese patients. (C) 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
Autores:
Cheng, Y.; Monteiro, C.; Matos, A.; et al.
Revista:
CLINICAL EPIGENETICS (ONLINE)
ISSN:
1868-7083
Año:
2018
Vol.:
10
Págs.:
54
BACKGROUND:
Periprostatic adipose tissue (PPAT) has been recognized to associate with prostate cancer (PCa) aggressiveness and progression. Here, we sought to investigate whether excess adiposity modulates the methylome of PPAT in PCa patients. DNA methylation profiling was performed in PPAT from obese/overweight (OB/OW, BMI¿>¿25 kg m-2) and normal weight (NW, BMI¿<¿25 kg m-2) PCa patients. Significant differences in methylated CpGs between OB/OW and NW groups were inferred by statistical modeling.
RESULTS:
Five thousand five hundred twenty-six differentially methylated CpGs were identified between OB/OW and NW PCa patients with 90.2% hypermethylated. Four hundred eighty-three of these CpGs were found to be located at both promoters and CpG islands, whereas the representing 412 genes were found to be involved in pluripotency of stem cells, fatty acid metabolism, and many other biological processes; 14 of these genes, particularly FADS1, MOGAT1, and PCYT2, with promoter hypermethylation presented with significantly decreased gene expression in matched samples. Additionally, 38 genes were correlated with antigen processing and presentation of endogenous antigen via MHC class I, which might result in fatty acid accumulation in PPAT and tumor immune evasion.
CONCLUSIONS:
Results showed that the whole epigenome methylation profiles of PPAT were significantly different in OB/OW compared to normal weight PCa patients. The epigenetic variation associated with excess adiposity likely resulted in altered lipid metabolism and immune dysregulation, contributing towards unfavorable PCa microenvironment, thus warranting further validation studies in larger samples.
Revista:
OBESITY
ISSN:
1930-7381
Año:
2018
Vol.:
26
N°:
4
Págs.:
672 - 682
ObjectiveThe objective of this study was to assess the utility of the 2-hour oral glucose tolerance test (OGTT) value to discriminate between different cardiometabolic profiles and examine the role of body composition in predicting the associated increased risk for glucose impairment, beta-cell dysfunction, and cardiovascular disease (CVD). MethodsSubjects with normal fasting glucose completed a 2-hour OGTT and were categorized to the carbohydrate metabolism alterations (CMAs) or the control group based on a 2-hour glucose threshold of 7.8 mmol/L. Body composition, visceral adipose tissue, OGTT-based parameters, and cardiovascular risk factors (CVRFs) such as hypertension, dyslipidemia, obstructive sleep apnea, nonalcoholic fatty liver disease, and smoking status were measured. ResultsSubjects with CMAs exhibited a significantly higher 1-hour postload glucose level and a greater decline in beta-cell function and CVRF profiles. After multivariate adjustment, an excess of total body and visceral fat was associated with an increased risk of CMAs, beta-cell dysfunction, CVRFs, and lower whole-body insulin sensitivity. ConclusionsThese data support the etiopathogenic role of body and visceral fat in the development of glucose derangements and CVRFs early on in the metabolic dysregulation process. Thus, body composition analysis and OGTT assessment performed in individuals with normal fasting glucose enable a better identification of patients at risk of developing type 2 diabetes and CVD.
Revista:
MOLECULAR NUTRITION AND FOOD RESEARCH
ISSN:
1613-4125
Scope: To investigate intestinal markers of iron absorption in morbidly obese subjects according to glucose tolerance. Methods and results: Gene expression of both non-heme (SLC40A1 (ferroportin), SLC11A2) and heme iron (SLC46A1 (HCP1), HMOX1) transporters is analyzed in 38 small intestine tissue samples [11 with normal glucose tolerance, 14 with glucose intolerance (GI), and 13 with newly diagnosed type 2 diabetes (T2D)]. SLC40A1 (r = 0.43, p = 0.008) and SLC11A2 (r = 0.35, p = 0.03) mRNA levels are positively correlated with ferritin-to-hepcidin ratio and with fasting glucose, being significantly increased in patients with T2D. Only ferroportin is negatively associated with serum hepcidin (r = -0.617, p < 0.0001). In multivariate regression analysis, fasting glucose contributes independently to intestinal SLC40A1 (p = 0.009) and SLC11A2 (p = 0.04) variance after controlling for age, sex, and BMI. When circulating hepcidin is incorporated into the model, fasting glucose contributes significantly and independently to intestinal SLC40A1 (p = 0.02), but not to SLC11A2 (p = 0.07) variance. SLC46A1 and HMOX1 are similar in all groups. Conclusion: The expression of ferroportin and SLC11A2 is increased in the intestine of patients with T2D in association with iron stores and serum hepcidin levels. Increased intestinal iron absorption is a potential mechanism that could explain the increased body iron stores frequently observed in patients with T2D.
Revista:
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN:
0014-2972
Año:
2018
Vol.:
48
N°:
Supl 1
Págs.:
6 - 7
Revista:
LANCET
ISSN:
0140-6736
Año:
2018
Vol.:
392
N°:
10161
Págs.:
2239 - 2240
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2018
Vol.:
41
N°:
2
Págs.:
287 - 289
Revista:
METABOLISM-CLINICAL AND EXPERIMENTAL
ISSN:
0026-0495
Año:
2018
Vol.:
87
Págs.:
123 - 135
Objective: Kallistatin plays an important role in the inhibition of inflammation, oxidative stress, fibrosis and angiogenesis. We aimed to determine the impact of kallistatin on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and oxidative stress.
Methods: Samples obtained from 95 subjects were used in a case-control study. Circulating concentrations and expression levels of kallistatin as well as key inflammation, oxidative stress and extracellular matrix remodelling-related genes were analyzed. Circulating kallistatin concentrations were measured before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB). The impact of kallistatin on lipopolysaccharide (LPS)- and tumour necrosis factor (TNF)-alpha-mediated inflammatory as well as oxidative stress signalling pathways was evaluated.
Results: We show that the reduced (P < 0.00001) circulating levels of kallistatin in obese patients increased (P < 0.00001) after RYGB. Moreover, gene expression levels of SERPINA4, the gene coding for kallistatin, were down regulated (P < 0.01) in the liver from obese subjects with non-alcoholic fatty liver disease. Additionally, we revealed that kallistatin reduced (P < 0.05) the expression of inflammation-related genes (CCL2, IL1B, IL6, IL8, TNFA, TGFB) and, conversely, upregulated (P < 0.05) mRNA levels of ADIPOQ and KLF4 in human adipocytes in culture. Kallistatin inhibited (P < 0.05) LPS- and INF-alpha-induced inflammation in human adipocytes via downregulating the expression and secretion of key inflammatory markers. Furthermore, kallistatin also blocked (P < 0.05) TNF-alpha-mediated lipid peroxidation as well as NOX2 and HIF1A expression while stimulating (P < 0.05) the. expression of SIRT1 and FOXO1.
Conclusions: These findings provide, for the first time, evidence of a novel role of kallistatin in obesity and its associated comorbidities by limiting adipose tissue inflammation and oxidative stress.
Revista:
LANCET DIABETES AND ENDOCRINOLOGY
ISSN:
2213-8587
Año:
2018
Vol.:
6
N°:
3
Págs.:
164 - 166
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2018
Vol.:
42
N°:
8
Págs.:
1458 - 1470
Background/Objectives: Obesity is related to a dynamic extracellular matrix (ECM) remodeling, which involves the synthesis and degradation of different proteins, such as tenascin C (TNC) in the adipose tissue (AT). Given the functional relationship between leptin and inducible nitric oxide synthase (iNOS), our aim was to analyze the impact of the absence of the iNOS gene in AT inflammation and ECM remodeling in ob/ob mice. Subjects/Methods: The expression of genes involved in inflammation and ECM remodeling was evaluated in 10-week-old male double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes as well as in ob/ob mice classified into three groups [control, leptin-treated (1 mg kg(-1) day(-1)) and pair-fed]. Results: Leptin deficiency increased inflammation and fibrosis in AT. As expected, leptin treatment improved the obesity phenotype. iNOS deficiency in ob/ob mice improved insulin sensitivity, AT inflammation, and ECM remodeling, as evidenced by lower AT macrophage infiltration and collagen deposition, a downregulation of proinflammatory and profibrogenic genes Tnf, Emr1, Hif1a, Col6a1, Col6a3, and Tnc, as well as lower circulating TNC levels. Interestingly, leptin upregulated TNC expression and release in 3T3-L1 adipocytes, and iNOS knockdown in 3T3-L1 fat cells produced a significant decrease in basal and leptin-induced Tnc expression. Conclusions: Ablation of iNOS in leptin-deficient mice improved AT inflammation and ECM remodeling-related genes, attenuating fibrosis, and metabolic dysfunction. The activation of iNOS by leptin is necessary for the synthesis and secretion of TNC in adipocytes, suggesting an important role of this alarmin in the development of AT inflammation and fibrosis.
Autores:
Travez, A.; Rabanal-Ruiz, Y. ; Lopez-Alcala, J. ; et al.
Revista:
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE (ONLINE)
ISSN:
1582-4934
Año:
2018
Vol.:
22
N°:
11
Págs.:
5648 - 5661
Adipocyte dysfunction in obesity is commonly associated with impaired insulin signalling in adipocytes and insulin resistance. Insulin signalling has been associated with caveolae, which are coated by large complexes of caveolin and cavin proteins, along with proteins with membrane-binding and remodelling properties. Here, we analysed the regulation and function of a component of caveolae involved in growth factor signalling in neuroendocrine cells, neuroendocrine long coiled-coil protein-2 (NECC2), in adipocytes. Studies in 3T3-L1 cells showed that NECC2 expression increased during adipogenesis. Furthermore, NECC2 co-immunoprecipitated with caveolin-1 (CAV1) and exhibited a distribution pattern similar to that of the components of adipocyte caveolae, CAV1, Cavin1, the insulin receptor and cortical actin. Interestingly, NECC2 overexpression enhanced insulin-activated Akt phosphorylation, whereas NECC2 downregulation impaired insulin-induced phosphorylation of Akt and ERK2. Finally, an up-regulation of NECC2 in subcutaneous and omental adipose tissue was found in association with human obesity and insulin resistance. This effect was also observed in 3T3-L1 adipocytes exposed to hyperglycaemia/hyperinsulinemia. Overall, the present study identifies NECC2 as a component of adipocyte caveolae that is regulated in response to obesity and associated metabolic complications, and supports the contribution of this protein as a molecular scaffold modulating insulin signal transduction at these membrane microdomains.
Revista:
MOLECULAR AND CELLULAR ENDOCRINOLOGY
ISSN:
0303-7207
Año:
2018
Vol.:
470
Págs.:
48 - 59
Insulin potentiates leptin effects on muscle accrual and glucose homeostasis. However, the relationship between leptin's central effects on peripheral insulin sensitivity and the associated structural changes remain unclear. We hypothesized that central leptin infusion modifies muscle size through activation of insulin signaling. Muscle insulin signaling, enzymes of fatty acid metabolism, mitochondrial respiratory chain complexes, proliferating cell nuclear antigen (PCNA) and fiber area were analyzed in the gastrocnemius of chronic central infused (L), pair-fed (PF) and control rats. PCNA-positive nuclei, fiber area, GLUT4 and glycogen levels and activation of Akt and mechanistic target of rapamycin were increased in L with no changes in PF. Acetyl-CoA carboxylase-beta mRNA levels and non-esterified fatty acid and triglyceride content were reduced and carnitine palmitoyltransferase-lb expression and mitochondrial complexes augmented in L These results suggest that leptin promotes an increase in muscle size associated with improved insulin signaling favored by lipid profile. (C) 2017 Elsevier B.V. All rights reserved.
Autores:
Fernandez-Garcia, J. C.; Alcaide, J.; Santiago-Fernandez, C.; et al.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2017
Vol.:
12
N°:
2
Págs.:
e0171204
Introduction Sensory factors may play an important role in the determination of appetite and food choices. Also, some adipokines may alter or predict the perception and pleasantness of specific odors. We aimed to analyze differences in smell-taste capacity between females with different weights and relate them with fat and fat-free mass, visceral fat, and several adipokines. Materials and methods 179 females with different weights (from low weight to morbid obesity) were studied. We analyzed the relation between fat, fat-free mass, visceral fat (indirectly estimated by bioelectrical impedance analysis with visceral fat rating (VFR)), leptin, adiponectin and visfatin. The smell and taste assessments were performed through the "Sniffin' Sticks" and "Taste Strips" respectively. Results We found a lower score in the measurement of smell (TDI-score (Threshold, Discrimination and Identification)) in obese subjects. All the olfactory functions measured, such as threshold, discrimination, identification and the TDI-score, correlated negatively with age, body mass index (BMI), leptin, fat mass, fat-free mass and VFR. In a multiple linear regression model, VFR mainly predicted the TDI-score. With regard to the taste function measurements, the normal weight subjects showed a higher score of taste functions. However a tendency to decrease was observed in the groups with greater or lesser BMI. In a multiple linear regression model VFR and age mainly predicted the total taste scores. Discussion We show for the first time that a reverse relationship exists between visceral fat and sensory signals, such as smell and taste, across a population with different body weight conditions.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2017
Vol.:
41
N°:
9
Págs.:
1379 - 1387
BACKGROUND/OBJECTIVES: Body weight, body mass index (BMI) and excess weight loss (EWL) are the most frequently used measures to analyse bariatric surgery outcomes. However, these measurements do not provide accurate information on body composition (BC) with body fat (BF), importantly determining the levels of cardiometabolic risk factors. Our aim was to analyse the evolution of BC after Roux-en-Y Gastric Bypass (RYGB) and its influence on the changes of cardiometabolic risk factors in comparison to BMI and EWL. SUBJECTS/METHODS: A group of 81 obese Caucasian patients (19 males/62 females) aged 44.9 +/- 1.3 years undergoing RYGB between January 2006 and December 2011 was prospectively followed up for a period of 3 years. BC was determined by air-displacement plethysmography. Visceral adiposity, physical activity and cardiometabolic risk factors were measured. RESULTS: BF was markedly (P < 0.001) reduced after the first year, increasing progressively during the second and third years after RYGB, following a different trajectory than body weight, BMI and EWL that decreased up to the second year post surgery. Markers of glucose homeostasis decreased during the first month and continued to decrease during the first year (P < 0.05), remaining stabilised or slightly increased between the second and third years following RYGB. However, markers of lipid metabolism decreased (P < 0.05) markedly during the first 12 months, increasing thereafter in parallel to the changes observed in BC, with the exception of high-density lipoprotein-cholesterol, which increased progressively throughout the whole period analysed. CONCLUSIONS: The adverse switch in the changes in BC between the first and the second years after RYGB may underlie the changes observed in cardiometabolic risk factors. Tracking of adiposity during the follow-up of bariatric/metabolic surgery yields clinically relevant information to better identify patients in need of increased lifestyle advice or treatment intensification.
Revista:
GUT
ISSN:
0017-5749
Año:
2017
Vol.:
66
N°:
10
Págs.:
1818 - 1828
Objective Fibroblast growth factor 15/19 (FGF15/19), an enterokine that regulates synthesis of hepatic bile acids (BA), has been proposed to influence fat metabolism. Without FGF15/19, mouse liver regeneration after partial hepatectomy (PH) is severely impaired. We studied the role of FGF15/19 in response to a high fat diet (HFD) and its regulation by saturated fatty acids. We developed a fusion molecule encompassing FGF19 and apolipoprotein A-I, termed Fibapo, and evaluated its pharmacological properties in fatty liver regeneration.
Design Fgf15¿/¿ mice were fed a HFD. Liver fat and the expression of fat metabolism and endoplasmic reticulum (ER) stress-related genes were measured. Influence of palmitic acid (PA) on FGF15/19 expression was determined in mice and in human liver cell lines. In vivo half-life and biological activity of Fibapo and FGF19 were compared. Hepatoprotective and proregenerative activities of Fibapo were evaluated in obese db/db mice undergoing PH.
Results Hepatosteatosis and ER stress were exacerbated in HFD-fed Fgf15¿/¿ mice. Hepatic expression of Ppar¿2 was elevated in Fgf15¿/¿ mice, being reversed by FGF19 treatment. PA induced FGF15/19 expression in mouse ileum and human liver cells, and FGF19 protected from PA-mediated ER stress and cytotoxicity. Fibapo reduced liver BA and lipid accumulation, inhibited ER stress and showed enhanced half-life. Fibapo provided increased db/db mice survival and improved regeneration upon PH.
Conclusions FGF15/19 is essential for hepatic metabolic adaptation to dietary fat being a physiological regulator of Ppar¿2 expression. Perioperative administration of Fibapo improves fatty liver regeneration.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2017
Vol.:
27
N°:
7
Págs.:
1763 - 1774
BACKGROUND:
Gastric plication is a minimally invasive bariatric surgical procedure, where the greater curvature is plicated inside the gastric lumen. Our aims were to analyze the effectiveness of gastric plication on the resolution of obesity, impaired glucose tolerance, and fatty liver in an experimental model of diet-induced obesity (DIO) and to evaluate changes in glycerol metabolism, a key substrate for adiposity and gluconeogenesis, in adipose tissue and the liver.
METHODS:
Male Wistar DIO rats (n = 58) were subjected to surgical (sham operation and gastric plication) or dietary interventions [fed a normal diet (ND) or high-fat diet (HFD) or pair-fed to the amount of food eaten by gastric-plicated animals]. The expression of aquaglyceroporins (AQPs) in epididymal (EWAT) and subcutaneous (SCWAT) fat and the liver was analyzed by real-time PCR and Western blot.
RESULTS:
Gastric plication did not result in a significant weight loss in DIO rats, showing a modest reduction in whole-body adiposity and hepatic steatosis. However, gastric-plicated animals exhibited an improvement in basal glycemia and glucose clearance, without changes in hepatic gluconeogenic genes. DIO was associated with an increase in glycerol, higher AQP3 and AQP7 in EWAT and SCWAT, and a decrease in hepatic AQP9. Gastric plication downregulated AQP3 in both fat depots without changes in adipose AQP7 and hepatic AQP9.
CONCLUSION:
Gastric plication results in a modest reduction in adiposity and hepatosteatosis but restores glycemia by downregulating AQP3, which entails lower efflux of glycerol from fat, lower plasma glycerol availability, and a reduced use of glycerol as a substrate for hepatic gluconeogenesis.
Revista:
DIABETOLOGIA
ISSN:
0012-186X
Año:
2017
Vol.:
60
N°:
5
Págs.:
915 - 926
Iron excess in adipose tissue is known to promote adipose tissue dysfunction. Here, we aimed to investigate the possible role of haem oxygenase 1 (HMOX1) in iron excess-induced adipose tissue dysfunction. Cross-sectionally, HMOX1 gene expression in subcutaneous and visceral adipose tissue was analysed in two independent cohorts (n = 234 and 40) in relation to obesity. We also evaluated the impact of weight loss (n = 21), weight gain (in rats, n = 20) on HMOX1 mRNA; HMOX1 mRNA levels during human adipocyte differentiation; the effects of inflammation and iron on adipocyte HMOX1; and the effects of HMOX1-induced activity on adipocyte mitochondrial respiratory function, glucose uptake and adipogenesis. Adipose tissue HMOX1 was increased in obese participants (p = 0.01) and positively associated with obesity-related metabolic disturbances, and markers of iron accumulation, inflammation and oxidative stress (p < 0.01). HMOX1 was negatively correlated with mRNAs related to mitochondrial biogenesis, the insulin signalling pathway and adipogenesis (p < 0.01). These associations were replicated in an independent cohort. Bariatric surgery-induced weight loss led to reduced HMOX1 (0.024 +/- 0.010 vs 0.010 +/- 0.004 RU, p < 0.0001), whereas in rats, high-fat diet-induced weight gain resulted in increased Hmox1 mRNA levels (0.22 +/- 0.15 vs 0.54 +/- 0.22 RU, p = 0.005). These changes were in parallel with changes in BMI and adipose tissue markers of iron excess, adipogenesis and inflammation. In human adipocytes, iron excess and inflammation led to increased HMOX1 mRNA levels. HMOX1 induction (by haem arginate [hemin] administration), resulted in a significant reduction of mitochondrial respiratory capacity (including basal respiration and spare respiratory capacity), glucose uptake and adipogenesis in parallel with increased expression of inflammatory- and iron excess-related genes. HMOX1 is an important marker of iron excess-induced adipose tissue dysfunction and metabolic disturbances in human obesity.
Revista:
OBESITY
ISSN:
1930-7381
Año:
2017
Vol.:
25
N°:
10
Págs.:
1723 - 1733
OBJECTIVE:
To investigate key enzymes of heme biosynthesis in human adipocytes and adipose tissue (AT).
METHODS:
Heme biosynthesis-related gene expression (ALAS1, ALAD, HMBS) was investigated in whole AT from humans (n¿=¿178 and n¿=¿75) and rats according to obesity status and during adipogenesis of human preadipocytes. The effects of aminotriazole (an ALAD inhibitor) and of ALAD knockdown were also studied.
RESULTS:
Consistent heme biosynthesis-related gene expression was detected in both subcutaneous AT (SAT) and visceral AT (VAT) and was significantly increased in SAT. ALAS1, ALAD, and HMBS mRNAs were positively associated with adipogenic gene expression in human AT and significantly decreased in subjects with obesity. These results were replicated in an independent cohort. Both SAT and VAT heme levels were positively correlated with ALAS1, ALAD, and HMBS mRNAs. ALAD and HMBS were mainly expressed in adipocytes and increased during differentiation of human adipocytes in parallel to adipogenic genes. In rats, high-fat diet-induced weight gain resulted in decreased Alad and Hmbs mRNAs in a similar way to what was observed with Adipoq. Aminotriazole administration or ALAD knockdown attenuated adipogenesis in parallel with decreased glucose uptake and impaired mitochondrial respiratory function during human adipocyte differentiation.
CONCLUSIONS:
Current data suggest a possible role of heme biosynthesis in human adipogenesis
Revista:
ONCOIMMUNOLOGY
ISSN:
2162-402X
Año:
2017
Vol.:
6
N°:
7
Págs.:
e1328338
Growing evidence indicates that adipose tissue inflammation is an important mechanism whereby obesity promotes cancer risk and progression. Since IL-32 is an important inflammatory and remodeling factor in obesity and is also related to colon cancer (CC) development, the aim of this study was to explore whether IL-32 could function as an inflammatory factor in human obesity-associated CC promoting a microenvironment favorable for tumor growth. Samples obtained from 84 subjects [27 lean (LN) and 57 obese (OB)] were used in the study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (49 without CC and 35 with CC). We show, for the first time, that obesity (p = 0.009) and CC (p = 0.026) increase circulating concentrations of IL-32¿. Consistently, we further showed that gene (p < 0.05) and protein (p < 0.01) expression levels of IL-32¿ were upregulated in VAT from obese patients with CC. Additionally, we revealed that IL32 expression levels are enhanced by hypoxia and inflammation-related factors in HT-29 CC cells as well as that IL-32¿ is involved in the upregulation of inflammation (IL8, TNF, and CCL2) and extracellular matrix (ECM) remodeling (SPP1 and MMP9) genes in HT-29 cancer cells. Additionally, we also demonstrate that the adipocyte-conditioned medium obtained from obese patients stimulates (p < 0.05) the expression of IL32 in human CC cells. These findings provide evidence of the potential involvement of IL-32 in the development of obesity-associated CC as a pro-inflammatory and ECM remodeling cytokine.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2017
Vol.:
7
N°:
1
Págs.:
5305
Iron status is known to be associated with the physiology of adipose tissue (AT). We aimed to investigate AT heme and expression of heme exporter (FLVCR1) in association with obesity and type 2 diabetes (T2D). Substantial amounts of FLVCR1 mRNA and protein levels were detected in AT, being significantly increased in subjects with T2D, and positively correlated with fasting glucose, fasting triglycerides and with circulating markers of iron stores (serum ferritin, blood hemoglobin and hematocrit). In both visceral (VAT) and subcutaneous AT (SAT), increased heme levels were found in subjects with T2D. Reinforcing these associations, FLVCR1 mRNA levels were positively linked to fasting glucose in an independent cohort. Longitudianlly, the percent change of FLVCR1 positively correlated with the percent change in fasting glucose (r = 0.52, p = 0.03) after bariatric surgery-induced weight loss. High-fat diet-induced weight gain in rats did not result in significant changes in AT Flvcr1 mRNA but, remarkably, the expression of this gene positively correlated with fasting glucose and negatively with insulin sensitivity (QUICKI). Altogether, these findings showed a direct association between FLVCR1 mRNA levels and hyperglycemia, suggesting that increased adipose tissue heme exportation might disrupt, or is the consequence of, impaired systemic glucose metabolism during the progression to T2D.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2017
Vol.:
7
N°:
1
Págs.:
6619
The aim of the present work was to study whether the leptin-adiponectin axis may have a pathophysiological role in the increased systemic inflammation and oxidative stress observed in patients with the metabolic syndrome (MS). Leptin, adiponectin, and markers of inflammation and oxidative stress were measured in a sample of 140 Caucasian subjects (74 males/66 females), aged 28-82 years, 60 with and 80 without the MS. Total concentrations of adiponectin as well as its multimeric forms HMW, MMW and LMW were significantly lower in individuals with the MS. The ratio adiponectin/leptin, a marker of dysfunctional adipose tissue, was dramatically decreased in the MS group. Systemic oxidative stress, as evidenced by levels of thiobarbituric acid reactive substances (TBARS), as well as markers of inflammation such as serum amyloid A (SAA), C-reactive protein (CRP) and osteopontin were significantly increased in subjects with the MS. Total adiponectin concentrations were negatively correlated with levels of TBARS and CRP levels. Furthermore, the ratio adiponectin/leptin was negatively correlated with SAA concentrations as well as with CRP levels. We concluded that a dysfunctional adipose tissue as suggested by a low adiponectin/leptin ratio may contribute to the increased oxidative stress and inflammation, hallmarks of the MS.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2017
Vol.:
7
N°:
1
Págs.:
2752
The circulating concentrations of adiponectin, an antidiabetic adipokine, have been shown to be reduced in obesity, in relation to an increase in inflammation. The aim of the present work was to assess the effect of leptin replacement on adiponectin levels and expression as well as on markers of oxidative stress and inflammation in leptin-deficient ob/ob mice. Twelve-week-old male mice (n=7-10 per group) were treated with either saline (wild type and ob/ob mice) or leptin (ob/ob mice) for 18 days. A third group of ob/ob mice was treated with saline and pair-fed to the amount of food consumed by the leptin-treated group. Leptin replacement restored values of adiponectin (P < 0.001), reduced circulating 8-isoprostane and serum amyloid A (SAA) levels (P < 0.05 for both), and significantly downregulated the increased gene expression of osteopontin (Spp1, P < 0.05), Saa3 (P < 0.05), Cd68 ( P < 0.01), Il6 (P < 0.01) and NADPH oxidase (Nox1 and Nox2, P < 0.01) in the perirenal WAT and Spp1 (P < 0.05) in the liver of ob/ ob mice. In cultured adipocytes from ob/ ob mice, leptin increased (P < 0.05) the mRNA expression and secretion of adiponectin. We concluded that circulating concentrations of adiponectin are positively regulated by leptin and ameliorate obesity-associated oxidative stress and inflammation in mice.
Revista:
CLINICAL AND EXPERIMENTAL PHARMACOLOGY & PHYSIOLOGY (ONLINE)
ISSN:
1440-1681
Año:
2017
Vol.:
44
N°:
3
Págs.:
386 - 394
We aimed to investigate the effects of two physical exercise models, voluntary physical activity (VPA) and endurance training (ET) as preventive and therapeutic strategies, respectively, on lipid accumulation regulators and mitochondrial content in VAT of rats fed a high-fat diet (HFD). Sprague-Dawley rats (6weeks old, n=60) were assigned into sedentary and VPA groups fed isoenergetic diets: standard (S, 35kcal% fat) or HFD (71kcal% fat). The VPA groups had free access to wheel running during the entire protocol. After 9weeks, half of the sedentary animals were exercised on a treadmill while maintaining the dietary treatments. The HFD induced no changes in plasma non-esterified fatty acids (NEFA) and glycerol levels and decreased oxidative phosphorylation (OXPHOS) subunit IV and increased truncated/full-length sterol regulatory element-binding transcription factor 1c (SREBP1c) ratio in epididymal white adipose tissue (eWAT). VPA decreased plasma glycerol levels, aquaglyceroporin 7 (AQP7) and increased subunit I of cytochrome c oxidase (COX) protein, in standard diet fed animals. Eight weeks of ET decreased body weight, visceral adiposity and adipocyte size and plasma NEFA and glycerol levels, as well as AQP7 protein expression in eWAT. ET increased fatty acid translocase (FAT/CD36), mitochondrial content of complexes IV and V subunits, mitochondrial biogenesis and dynamic (mitofusins and optic atrophy 1)-related proteins. Moreover, lipogenesis-related markers (SREBP1c and acetyl CoA carboxylase) were reduced after 8weeks of ET. In conclusion, ET-induced alterations reflect a positive effect on mitochondrial function and the overall VAT metabolism of HFD-induced obese rats.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2017
Vol.:
41
N°:
9
Págs.:
1394 - 1402
BACKGROUND/OBJECTIVES: Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues as well as for pancreatic insulin secretion. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in beta-cells, and AQP12, an aquaporin related to pancreatic damage, in the improvement of pancreatic function and steatosis after sleeve gastrectomy in diet-induced obese rats. SUBJECTS/METHODS: Male Wistar obese rats (n = 125) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by sleeve-gastrectomized animals) interventions. The tissue distribution and expression of AQPs in the rat pancreas were analyzed by real-time PCR, western blotting and immunohistochemistry. The effect of ghrelin isoforms and glucagon-like peptide 1 (GLP-1) on insulin secretion, triacylglycerol (TG) accumulation and AQP expression was determined in vitro in RIN-m5F beta-cells. RESULTS: Sleeve gastrectomy reduced pancreatic beta-cell apoptosis, steatosis and insulin secretion. Lower ghrelin and higher GLP-1 concentrations were also found after bariatric surgery. Acylated and desacyl ghrelin increased TG content, whereas GLP-1 increased insulin release in RIN-m5F beta-cells. Sleeve gastrectomy was associated with an upregulation of AQP7 together with a normalization of the increased AQP12 levels in the rat pancreas. Interestingly, ghrelin and GLP-1 repressed AQP7 and AQP12 expression in RINm5F beta-cells. AQP7 protein was negatively correlated with intracellular lipid accumulation in acylated ghrelin-treated cells and with insulin release in GLP-1-stimulated beta-cells. CONCLUSIONS: AQP7 upregulation in beta-cells after sleeve gastrectomy contributes, in part, to the improvement of pancreatic steatosis and insulin secretion by increasing intracellular glycerol used for insulin release triggered by GLP-1 rather than for ghrelin-induced TG biosynthesis.
Autores:
Blundell, J. E.; Baker, J. L.; Boyland, E.; et al.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2017
Vol.:
10
N°:
1
Págs.:
25 - 37
Over the last 10 years the prevalence of obesity across the European continent has in general been rising. With the exception of a few countries where a levelling-off can be perceived, albeit at a high level, this upward trend seems likely to continue. However, considerable country to country variation is noticeable, with the proportion of people with obesity varying by 10% or more. This variation is intriguing and suggests the existence of different profiles of risk or protection factors operating in different countries. The identification of such protection factors could indicate suitable targets for interventions to help manage the obesity epidemic in Europe. This report is the output of a 2-day workshop on the 'Diversity of Obesity in Europe'. The workshop included 14 delegates from 12 different European countries. This report contains the contributions and discussions of the materials and viewpoints provided by these 14 experts; it is not the output of a single mind. However, such is the nature of scientific analysis regarding obesity that it is possible that a different set of 14 experts may have come to a different set of conclusions. Therefore the report should not be seen as a definitive statement of a stable situation. Rather it is a focus for discussion and comment, and a vehicle to drive forward further understanding and management of obesity in Europe.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2016
Vol.:
6
Págs.:
39942
Bariatric surgery improves non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the potential role of ghrelin isoforms in the resolution of hepatic steatosis after sleeve gastrectomy, a restrictive bariatric surgery procedure, in diet-induced obese rats. Male Wistar rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal (ND) or a high-fat (HFD) diet or pair-fed]. Obese rats developed hepatosteatosis and showed decreased circulating desacyl ghrelin without changes in acylated ghrelin. Sleeve gastrectomy induced a dramatic decrease of desacyl ghrelin, but increased the acylated/desacyl ghrelin ratio. Moreover, sleeve gastrectomy reduced hepatic triglyceride content and lipogenic enzymes Mogat2 and Dgat1, increased mitochondrial DNA amount and induced AMPK-activated mitochondrial FFA beta-oxidation and autophagy to a higher extent than caloric restriction. In primary rat hepatocytes, the incubation with both acylated and desacyl ghrelin (10, 100 and 1,000 pmol/L) significantly increased TG content, triggered AMPK-activated mitochondrial FFA beta-oxidation and autophagy. Our data suggest that the decrease in the most abundant isoform, desacyl ghrelin, after sleeve gastrectomy contributes to the reduction of lipogenesis, whereas the increased relative acylated ghrelin levels activate factors involved in mitochondrial FFA beta-oxidation and autophagy in obese rats, thereby ameliorating NAFLD.
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2016
Vol.:
101
N°:
10
Págs.:
3803-3811
We conclude that serum ANGPTL8/betatrophin concentrations are altered in human dyslipidemia. ANGPTL8/betatrophin emerges as a potential player in dyslipidemia with a strong association with HDL-cholesterol and a potential therapeutic tool for the treatment of dyslipidemia.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2016
Vol.:
26
N°:
8
Págs.:
1881-9
Our study showed that serum ANGPTL8/betatrophin concentrations were increased in obese subjects after surgically induced weight loss, but not after weight loss achieved by conventional dietary treatment. The change in ANGPTL8/betatrophin concentrations emerged as a significant predictor of the change in HDL-C levels after weight loss.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2016
Vol.:
26
N°:
2
Págs.:
282 - 288
Background: Current evidence suggests that local anesthetic wound infiltration should be employed as part of multimodal postoperative pain management. There is scarce data concerning the benefits of this anesthetic modality in laparoscopic weight loss surgery. Therefore, we analyzed the influence of trocar site infiltration with bupivacaine on the management of postoperative pain in laparoscopic bariatric surgery.
Methods: This retrospective randomized study included 47 patients undergoing primary obesity surgery between January and September 2014. Laparoscopic gastric bypass was performed in 39 cases and sleeve gastrectomy in 8 cases. Patients were stratified into two groups depending on whether preincisional infiltration with bupivacaine and epinephrine was performed (study group, 27 patients) or not (control group, 20 patients). Visual analogue scale (VAS), International Pain Outcomes questionnaire, and rescue medication records were reviewed to assess postoperative pain.
Results: VAS scores in the study group and sleeve gastrectomy group were lower than those in the control and gastric bypass groups in the first 4 h postoperatively without reaching statistical significance (p > 0.05). VAS scores did not differ in any other period of time. No statistically significant differences in pain perception were registered according to the patient's pain outcomes questionnaire or the need for rescue medication.
Conclusions: The present study did not conclusively prove the efficacy of bupivacaine infiltration by any of the three evaluation methods analyzed. Nevertheless, preincisional infiltration provides good level of comfort in the immediate postoperative period when analgesia is most urgent.
Revista:
ENDOCRINOLOGY
ISSN:
0013-7227
Año:
2016
Vol.:
157
N°:
9
Págs.:
3391-3
Revista:
CLINICAL NUTRITION
ISSN:
0261-5614
Año:
2016
Vol.:
36
N°:
3
Págs.:
861 - 868
BACKGROUND & AIMS:
Fibroblast growth factor 19 (FGF19) and 21 (FGF21) have emerged as key regulators of energy homeostasis. Our aim was to analyze the impact of weight loss (WL) induced either by conventional dietary treatment (CDT) or bariatric surgery on FGF19 and FGF21 concentrations. Furthermore, the diverse effect of sleeve gastrectomy (SG) versus RYGB (Roux-en-Y gastric bypass) as two surgical procedures that affect the gastrointestinal anatomy and physiology differently was also analyzed.
METHODS:
Serum concentrations of FGF19 and FGF21 were measured in 137 obese patients with different degrees of insulin resistance matched by sex, age and body adiposity and compared to 33 lean individuals. Furthermore, FGF19 and FGF21 were measured in 114 subjects before and one-year after WL induced either by CDT (n = 28), SG (n = 20) or RYGB (n = 66).
RESULTS:
Circulating serum FGF19 concentrations were decreased (P < 0.01) similarly in obese patients regardless of their degree of insulin resistance, while FGF21 levels were increased in obesity (P < 0.01), being further increased in obesity-associated T2D (P < 0.01). FGF19 concentrations were increased in obese subjects after surgically-induced WL (P < 0.01), but not after WL achieved by CDT, while FGF21 levels were reduced after CDT- (P < 0.05) or SG-induced WL (P < 0.05), but not after RYGB. The change in FGF21 concentrations emerged as a significant predictor of the change in insulin resistance (HOMA) after WL.
CONCLUSIONS:
Based on the circulating concentrations and their subsequent pattern of response following WL, we conclude that FGF19 levels are mainly related to body adiposity, in particular visceral adiposity, while FGF21 is mainly related to glucose homeostasis. CLINICALTRIALS.
GOV IDENTIFIER:
NCT01572090.
Revista:
EUROPEAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
ISSN:
0954-691X
Año:
2016
Vol.:
28
N°:
2
Págs.:
139 - 145
Objective Hypermetabolism in cirrhosis is associated with a high risk of complications and mortality. However, studies about underlying mechanisms are usually focussed on isolated potential determinants and specific etiologies, with contradictory results. We aimed at investigating differences in nutrition, metabolic hormones, and hepatic function between hypermetabolic and nonhypermetabolic men with cirrhosis of the liver. Patients and methods We prospectively enrolled 48 male cirrhotic inpatients. We evaluated their resting energy expenditure (REE) and substrate utilization by indirect calorimetry, body composition by dual-energy X-ray absorptiometry, liver function, and levels of major hormones involved in energy metabolism by serum sample tests. Patients with ascites, specific metabolic disturbances, and hepatocellular carcinoma were excluded. Results REE and REE adjusted per fat-free mass (FFM) were significantly increased in cirrhotic patients. Overall, 58.3% of cirrhotic patients were classified as hypermetabolic. Groups did not differ significantly in age, etiology of cirrhosis, liver function, presence of ascites, use of diuretics, â-blockers, or presence of transjugular intrahepatic portosystemic shunts. Hypermetabolic cirrhotic patients had lower weight, BMI (P< 0.05), nonprotein respiratory quotient (P< 0.01), leptin (P<0.05), and leptin adjusted per fat mass (FM) (P<0.05), but higher FFM% (P< 0.05) and insulin resistance [homeostatic model assessment-insulin resistance (HOMA-IR)] (P<0.05). Only HOMA-IR, leptin/FM, and FFM% were independently related to the presence of hypermetabolism. Conclusion Hypermetabolic cirrhotic men are characterized by lower weight, higher FFM%, insulin resistance, and lower leptin/FM when compared with nonhypermetabolic men. HOMA-IR, FFM%, and leptin/FM were independently associated with hypermetabolism, and may serve as easily detectable markers of this condition in daily clinical practice.
Revista:
MOLECULAR NUTRITION & FOOD RESEARCH (ONLINE)
ISSN:
1613-4133
Año:
2016
Vol.:
60
N°:
7
Págs.:
1673-83
Current data reinforce the impact of TAS2R38 gene on phenotypic and clinical outputs affecting obesity, showing significant associations with extreme weight conditions (i.e., obesity and anorexia nervosa), and changes in both olfactory capacity and immune traits.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2016
Vol.:
40
N°:
9
Págs.:
1405 - 1415
Background/Objectives:Uroguanylin and guanylin are secreted by intestinal epithelial cells as prohormones postprandially and act on the hypothalamus to induce satiety. The impact of obesity and obesity-associated type 2 diabetes (T2D) on proguanylin and prouroguanylin expression/secretion as well as the potential role of guanylin and uroguanylin in the control of lipolysis in humans was evaluated.Subjects/Methods:Circulating and gastrointestinal expression of proguanylin (GUCA2A) and prouroguanylin (GUCA2B) were measured in 134 subjects. In addition, plasma proguanylin and prouroguanylin were measured before and after weight loss achieved either by Roux-en-Y gastric bypass (RYGB) (n=24) or after a conventional diet (n=15). The effect of guanylin and uroguanylin (1¿100¿nmol¿l-1) on lipolysis was determined in vitro in omental adipocytes.Results:Circulating concentrations of prouroguanylin, but not proguanylin, were decreased in obesity in relation to adiposity. Weight loss achieved by RYGB increased plasma proguanylin and prouroguanylin. Obese T2D individuals showed higher expression of intestinal GUCA2A as well as of the receptors of the guanylin system, GUCY2C and GUCY2D, in omental adipocytes. The incubation with guanylin and uroguanylin significantly stimulated lipolysis in differentiated omental adipocytes, as evidenced by hormone-sensitive lipase phosphorylation at Ser563, an increase in fatty acids and glycerol release together with an upregulation of several lipolysis-related genes, including AQP3, AQP7, FATP1 or CD36.Conclusions:Both guanylin and uroguanylin trigger lipolysis in human visceral adipocytes. Given the lipolytic action of the guanylin system on visceral adipocytes, the herein reported decrease of circulating prouroguanylin concentrations in obese patients may have a role in excessive fat accumulation in obesity
Revista:
DIABETES
ISSN:
0012-1797
Año:
2016
Vol.:
65
N°:
12
Págs.:
3636 - 3648
Interleukin (IL)-32 is a recently described cytokine involved in the regulation of inflammation. We aimed to explore whether IL-32 could function as an inflammatory and angiogenic factor in human obesity and obesity-associated type 2 diabetes. Samples obtained from 90 subjects were used in the study. Obese patients exhibited higher expression levels of IL-32 in visceral adipose tissue (AT) as well as in subcutaneous AT and peripheral blood mononuclear cells. IL32 was mainly expressed by stromovascular fraction cells, and its expression was significantly enhanced by inflammatory stimuli and hypoxia, whereas no changes were found after the incubation with anti-inflammatory cytokines. The addition of exogenous IL-32 induced the expression of inflammation and extracellular matrix¿related genes in human adipocyte cultures, and IL32-silenced adipocytes showed a downregulation of inflammatory genes. Furthermore, adipocyte-conditioned media obtained from obese patients increased IL32 gene expression in human monocyte cultures, whereas the adipocyte-conditioned media from lean volunteers had no effect on IL32 mRNA levels. These findings provide evidence, for the first time, about the inflammatory and remodeling properties of IL-32 in AT, implicating this cytokine in obesity-associated comorbidities.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2016
Vol.:
11
N°:
9
Págs.:
e0162189
To our knowledge, we herein show for the first time that obese patients with CC exhibit increased circulating levels of OPN, YKL-40 and TNC providing further evidence for the influence of obesity on CC development via ECM proteins, representing promising diagnostic biomarkers or target molecules for therapeutics.
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2016
Vol.:
39
N°:
1
Págs.:
23 - 33
Revista:
TRENDS IN ENDOCRINOLOGY AND METABOLISM
ISSN:
1043-2760
Año:
2016
Vol.:
27
N°:
10
Págs.:
678 - 680
A Joint Statement endorsed by 45 international organizations, clinicians, and researchers indicating when to recommend or consider metabolic surgery in type 2 diabetes mellitus (T2DM) treatment has been recently published. These new guidelines, resulting from the Second Diabetes Surgery Summit (DSS-II), represent the most radical change in T2DM management of the past few decades.
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2016
Vol.:
39
N°:
1
Págs.:
105 - 114
Background: There is a high prevalence of nutritional disorders in patients with liver cirrhosis (LC). This study was designed to assess the relationships between liver function, IFG-I/IGFBP-3, nutritional status, leptin, ghrelin and glucagon in 21 patients waiting for liver transplantation (LT).
Methods: We studied 21 men aged 56±2.1 years who were on the LT list. They were classified according to Child-Pugh(CP) score from low to high liver dysfunction in CPA (n=4),CPB (n=11) and CPC (n=6). Body mass index (BMI) was calculated and body fat (%) was measured by air-displacement plethysmography. Resting energy expenditure (REE) and its variation over Harris-Benedict values (GER%) were assessed by indirect calorimetry. Fasting serum samples were taken to measure albumin, glucose, insulin, HbA1c, leptin, total ghrelin,glucagon, IGF-I and IGFBP3.
Results: There were no differences in fat % and leptin values in the three groups according to CP classification. The CPC group showed higher ghrelin values than CPA and CPB(p<0.05). All groups displayed high glucagon levels and GER%values superior to 100%. Positive correlations were found between glucagon and GER% (r=0.56; p<0.01) and between glucagon and ghrelin values (r=0.66; p<0.01). IGF-I and IGFBP3 were low in all groups and showed a positive correlation with plasma albumin (r=0.52; p<0.05 and r=0.45; p<0.05 respectively).
Conclusions: These results show an increase in ghrelin plasma values in patients with severe liver dysfunction. Hyperglucagonemia was correlated with GER%, supporting a role of glucagon in the hypermetabolic state associated to LC,raising the possibility of becoming a therapeutic target. The measurement of IGF-I/IGFBP3 represents a good marker of liver function in patients with LC.
Autores:
Sarah; Susana; Isabel; et al.
Revista:
PSYCHONEUROENDOCRINOLOGY
ISSN:
0306-4530
Año:
2016
Vol.:
65
N°:
2016
Págs.:
102-108
Plasma orexin-A concentrations contribute to poor sleep quality in AN, and both of these variables are associated with therapy response.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2016
Vol.:
26
N°:
7
Págs.:
1549-58
Background
Aging and obesity are two conditions associated with increased risk of cardiovascular disease. Our aim was to analyze whether an advanced age affects the beneficial effects of sleeve gastrectomy on weight loss and blood pressure in an experimental model of diet-induced obesity (DIO).
Methods
Young (6-month-old) and old (18-month-old) male Wistar DIO rats (n¿=¿101) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions (pair-fed to the amount of food eaten by sleeve gastrectomized animals). Systolic (SBP), diastolic (DBP), and mean (MBP) blood pressure values and heart rate (HR) were recorded in conscious, resting animals by non-invasive tail-cuff plethysmography before and 4 weeks after surgical or dietary interventions.
Results
Aging was associated with higher (P¿<¿0.05) body weight and subcutaneous and perirenal fat mass as well as mild cardiac hypertrophy. Sleeve gastrectomy induced a reduction in body weight, whole-body adiposity, and serum total ghrelin in both young and old DIO rats. The younger group achieved a higher excess weight loss than the older group (164¿±¿60 vs. 82¿±¿17 %, P¿<¿0.05). A significant (P¿<¿0.05) decrease in insulin resistance, SBP, DBP, MBP, and HR without changes in heart weight was observed after sleeve gastrectomy independently of age.
Conclusion
Our results provide evidence for the effectiveness of sleeve gastrectomy without increased operative risk in body weight and blood pressure reduction
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2016
Vol.:
26
N°:
7
Págs.:
1537-48
Background: Susceptibility to obesity is associated with a notable inter-individual variation. The aim of the present study was to compare the effectiveness of sleeve gastrectomy (SG) on weight loss and metabolic profile in obesity-prone (OP) rats vs animals that are non-susceptible to obesity (NSO). Methods: Young male Wistar rats (n = 101) were put in a diet-induced obesity (DIO) programme with ad libitum access to a high-fed diet (HFD) during 12 months. Body weight and food intake were regularly registered. Thereafter, rats were ranked by final body weight to identify the obesity-prone (OP) (n = 13) and non-susceptible to obesity (NSO) (n = 14) animals. OP and NSO rats were submitted to surgical interventions (sham operation, SG and pair-fed to the amount of food eaten by sleeve-gastrectomized rats). Body weight, food intake, energy expenditure, body temperature, fat pads weight, and metabolic profiling were analysed 4 weeks after surgical or dietary interventions. Results: SG in both OP and NSO rats decreased body weight as compared to sham and pair-fed groups (P < 0.05), mainly due to reductions in subcutaneous and perirenal fat mass (P < 0.001). Total weight loss achieved in sleeve-gastrectomized OP and NSO rats was higher than that of pair-fed ones (P < 0.05), showing that the SG effect goes beyond caloric restriction. In this regard, sleeve-gastrectomized rats exhibited significantly (P < 0.05) increased basal rectal temperature together with upregulated brown adipose tissue Ucp-1 protein expression levels. A significant (P < 0.05) improvement in insulin sensitivity was also observed in both OP and NSO animals that underwent SG as compared with pair-fed counterparts. Conclusion: Our findings provide the first evidence that obesity-prone rats also benefit from surgery responding effectively to SG, as evidenced by the significant body weight reduction and the metabolic profile improvement.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2015
Vol.:
25
N°:
9
Págs.:
1594-1603
The present study provides evidence for the existence of an adverse cardiometabolic profile in subjects currently considered to be outside traditional NIH guidelines but exhibiting a highly increased adiposity. It is concluded that body composition analysis yields valuable information to be incorporated into indication criteria for BS and that adiposity may be an independent indicator for BS.
Revista:
MOLECULAR AND CELLULAR ENDOCRINOLOGY
ISSN:
0303-7207
Año:
2015
Vol.:
415
Págs.:
157-172
Leptin and insulin use overlapping signaling mechanisms to modify hepatic glucose metabolism, which is critical in maintaining normal glycemia. We examined the effect of an increase in central leptin and insulin on hepatic glucose metabolism and its influence on serum glucose levels. Chronic leptin infusion increased serum leptin and reduced hepatic SH-phosphotyrosine phosphatase 1, the association of suppressor of cytokine signaling 3 to the insulin receptor in liver and the rise in glycemia induced by central insulin. Leptin also decreased hepatic phosphoenolpyruvate carboxykinase levels and increased insulin's ability to phosphorylate insulin receptor substrate-1, Akt and glycogen synthase kinase on Ser9 and to stimulate glucose transporter 2 and glycogen levels. Peripheral leptin treatment reproduced some of these changes, but to a lesser extent. Our data indicate that leptin increases the hepatic response to a rise in insulin, suggesting that pharmacological manipulation of leptin targets may be of interest for controlling glycemia.
Revista:
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
ISSN:
0735-1097
Año:
2015
Vol.:
65
N°:
6
Págs.:
622-623
Revista:
ACTA DIABETOLOGICA
ISSN:
0940-5429
Año:
2015
Vol.:
52
N°:
2
Págs.:
257-266
The ribosomal protein S6 kinase 1 (S6K1) is a component of the insulin signalling pathway that has been proposed as a key molecular factor in insulin resistance development under conditions of nutrient overload. The aim was to evaluate the involvement of S6K1 in obesity as well as to explore their association with visceral adipose tissue (VAT) inflammation. Samples obtained from 40 subjects were used. Gene expression levels of RPS6KB1 and key inflammatory markers were analysed in VAT. The effect of insulin on transcript levels of RPS6KB1 in human differentiated adipocytes was also explored. RPS6KB1 mRNA levels in VAT were increased (P < 0.05) in obese patients. Insulin treatment significantly enhanced (P < 0.01) gene expression levels of RPS6KB1 and a positive association (P < 0.05) of RPS6KB1 expression with different markers of insulin resistance was observed. Moreover, RPS6KB1 gene expression levels were positively correlated with VAT gene expression levels of the inflammatory markers CCL2, CD68, MMP2, MMP9, VEGFA and CHI3L1 as well as with mRNA levels of MTOR and MAPK8, representative players involved in signalling pathways related to S6K1. The increased levels of S6K1 in obesity and its positive association with insulin resistance and inflammation suggest a role for this protein in the changes that take place in VAT in obesity establishing a link between inflammation and a higher risk for the development of metabolic
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2015
Vol.:
39
N°:
3
Págs.:
397-407
Taken together, our results provide evidence for a regulatory role of leptin on FNDC5/irisin, favoring muscle accretion but reducing fat browning
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2015
Vol.:
5
Págs.:
12067
Glycerol is an important metabolite for the control of lipid accumulation in white adipose tissue (WAT) and liver. We aimed to investigate whether exogenous administration of leptin improves features of non-alcoholic fatty liver disease (NAFLD) in leptin-deficient ob/ob mice via the regulation of AQP3 and AQP7 (glycerol channels mediating glycerol efflux in adipocytes) and AQP9 (aquaglyceroporin facilitating glycerol influx in hepatocytes). Twelve-week-old male wild type and ob/ob mice were divided in three groups as follows: control, leptin-treated (1 mg/kg/d) and pair-fed. Leptin deficiency was associated with obesity and NAFLD exhibiting an AQP3 and AQP7 increase in WAT, without changes in hepatic AQP9. Adipose Aqp3 and hepatic Aqp9 transcripts positively correlated with markers of adiposity and hepatic steatosis. Chronic leptin administration (4-weeks) was associated with improved body weight, whole-body adiposity, and hepatosteatosis of ob/ob mice and to a down-regulation of AQP3, AQP7 in WAT and an up-regulation of hepatic AQP9. Acute leptin stimulation in vitro (4-h) induced the mobilization of aquaglyceroporins towards lipid droplets (AQP3) and the plasma membrane (AQP7) in murine adipocytes. Our results show that leptin restores the coordinated regulation of fat-specific AQP7 and liver-specific AQP9, a step which might prevent lipid overaccumulation in WAT and liver in obesity
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2015
Vol.:
39
N°:
1
Págs.:
121-9
Obesity is characterized by reciprocal alterations in FGF19 (decrease) and FGF21 (increase) levels. Although worsened in diabetic obese patients, obesity itself appears as the predominant determinant of the abnormalities in FGF21 and FGF19 levels. Opposite changes in ß-Klotho expression in fat and liver indicate potential tissue-specific alterations in the responsiveness to endocrine FGFs in obesity
Revista:
GENES AND NUTRITION
ISSN:
1555-8932
Año:
2015
Vol.:
10
N°:
3
Págs.:
460
Inflammation is a critical contributor to the pathogenesis of metabolic disorders with adipose tissue being crucial in the inflammatory response by releasing multiple adipokines with either pro- or anti-inflammatory activities with potential functions as metabolic regulators. Peripheral blood mononuclear cells (PBMC) have been proposed as representative of the inflammatory status in obesity. The aim of the present study was to evaluate the contribution of PBMC to the obesity-associated chronic inflammation analyzing the expression of novel adipokines. Samples obtained from 69 subjects were used in the study. Real-time PCR determinations were performed to quantify gene expression levels in PBMC of novel adipokines including chemerin, chitinase-3-like protein 1 (YKL-40), lipocalin-2 (LCN-2) and osteopontin (OPN), and their circulating concentrations were also determined by ELISA. We show, for the first time, that PBMC gene expression levels of chemerin (P < 0.0001), chitinase-3-like protein 1 (P = 0.010), lipocalin-2 (P < 0.0001) and osteopontin (P < 0.0001) were strongly upregulated in obesity independently of the glycemic state. Circulating concentrations of these adipokines followed the same trend being significantly higher (P < 0.05) in obese normoglycemic and type 2 diabetic patients compared to lean volunteers and also associated (P < 0.05) with their corresponding mRNA levels in PBMC. These results provide evidence that alterations in inflammation-related adipokines are
Revista:
GENES AND NUTRITION
ISSN:
1555-8932
Año:
2015
Vol.:
10
N°:
3
Págs.:
460
Inflammation is a critical contributor to the pathogenesis of metabolic disorders with adipose tissue being crucial in the inflammatory response by releasing multiple adipokines with either pro- or anti-inflammatory activities with potential functions as metabolic regulators. Peripheral blood mononuclear cells (PBMC) have been proposed as representative of the inflammatory status in obesity. The aim of the present study was to evaluate the contribution of PBMC to the obesity-associated chronic inflammation analyzing the expression of novel adipokines. Samples obtained from 69 subjects were used in the study. Real-time PCR determinations were performed to quantify gene expression levels in PBMC of novel adipokines including chemerin, chitinase-3-like protein 1 (YKL-40), lipocalin-2 (LCN-2) and osteopontin (OPN), and their circulating concentrations were also determined by ELISA. We show, for the first time, that PBMC gene expression levels of chemerin (P < 0.0001), chitinase-3-like protein 1 (P = 0.010), lipocalin-2 (P < 0.0001) and osteopontin (P < 0.0001) were strongly upregulated in obesity independently of the glycemic state. Circulating concentrations of these adipokines followed the same trend being significantly higher (P < 0.05) in obese normoglycemic and type 2 diabetic patients compared to lean volunteers and also associated (P < 0.05) with their corresponding mRNA levels in PBMC. These results provide evidence that alterations in inflammation-related adipokines are
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2015
Vol.:
25
N°:
9
Págs.:
1723 - 1734
BACKGROUND:
Glycerol constitutes an important metabolite for the control of lipid accumulation and glucose homeostasis. Our aim was to investigate the potential role of aquaglyceroporins, which are glycerol channels mediating glycerol efflux in adipocytes (AQP3 and AQP7) and glycerol influx (AQP9) in hepatocytes, in the improvement of adiposity and hepatic steatosis after sleeve gastrectomy in an experimental model of diet-induced obesity (DIO).
METHODS:
Male Wistar DIO rats (n = 161) were subjected to surgical (sham operation and sleeve gastrectomy) or dietary interventions [fed ad libitum a normal diet (ND) or a high-fat diet (HFD) or pair-fed to the amount of food eaten by sleeve-gastrectomized animals]. The tissue distribution and expression of AQPs in biopsies of epididymal (EWAT) and subcutaneous (SCWAT) white adipose tissue and liver were analyzed by real-time PCR, Western blot, and immunohistochemistry.
RESULTS:
Four weeks after surgery, DIO rats undergoing sleeve gastrectomy showed a reduction in body weight, whole-body adiposity, and hepatic steatosis. DIO was associated with a tendency towards an increase in EWAT AQP3 and SCWAT AQP7 and a decrease in hepatic AQP9. Sleeve gastrectomy downregulated AQP7 in both fat depots and upregulated AQP3 in EWAT, without changing hepatic AQP9. Aqp7 transcript levels in EWAT and SCWAT were positively associated with adiposity and glycemia, while Aqp9 mRNA was negatively correlated with markers of hepatic steatosis and insulin resistance.
CONCLUSION:
Our results show, for the first time, that sleeve gastrectomy, a widely applied bariatric surgery procedure, restores the coordinated regulation of fat-specific AQP7 and liver-specific AQP9, thereby improving whole-body adiposity and hepatic steatosis.
Revista:
ARCHIVES OF MEDICAL RESEARCH
ISSN:
0188-4409
Año:
2015
Vol.:
46
N°:
1
Págs.:
47-53
Increased STX8 expression in VAT appears to be associated with the presence of T2D in obese patients through a mechanism that may involve GLUT4.
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2014
Vol.:
99
N°:
8
Págs.:
E1407 - E1417
CONTEXT:
Wingless-type mouse mammary tumor virus integration site family (WNT)-5A is a glycoprotein involved in the regulation of the inflammatory response by activating the noncanonical Wnt signaling pathway. Secreted frizzled-related protein (SFRP)-5 acts as a decoy receptor that binds and sequesters WNT5A, preventing activation of frizzled receptors and attenuating the noncanonical Wnt signaling.
OBJECTIVE:
The aim of the study was to evaluate the involvement of WNT5A and SFRP5 in obesity and obesity-related comorbidities as well as to explore their effect in visceral adipose tissue inflammation.
PATIENTS AND METHODS:
Samples obtained from 90 subjects were used. Circulating and gene expression levels of WNT5A and SFRP5 were analyzed in different metabolic tissues. The effect of TNF-¿ and lipopolysaccharide on the transcript levels of WNT5A and SFRP5 in adipocytes was explored. We also investigated whether WNT5A itself can activate an inflammatory response.
RESULTS:
Increased circulating levels of WNT5A in obese patients (P < .05) were decreased (P < .001) after gastric bypass. In this line, WNT5A mRNA in visceral adipose tissue was increased (P < .05) in obese patients with gene expression levels of SFRP5 being down-regulated (P < .05). WNT5A mRNA expression was significantly enhanced (P < .01) by lipopolysaccharide and TNF-¿ treatment, whereas no effects were found in SFRP5 gene expression levels. Furthermore, exogenous WNT5A induced (P < .05) IL-6, IL1B, MMP2, MMP9, and SSP1 mRNA expression in human adipocyte cultures.
CONCLUSIONS:
Activation of noncanonical Wnt signaling through the up-regulation of WNT5A and down-regulation of SFRP5 may promote a proinflammatory state in visceral adipose tissue contributing to the development of obesity-associated comorbidities.
Autores:
Sini; Lilli; Naukkarinen; et al.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2014
Vol.:
38
N°:
11
Págs.:
1423-1431
Together, hypertrophy and hypoplasia in acquired obesity are related to metabolic dysfunction, possibly through disturbances in mitochondrial function and increased cell death within the adipose tissue.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2014
Vol.:
38
N°:
12
Págs.:
1545-54
These findings show, for the first time, that HMGB1 expression and release by human adipocytes is altered by inflammatory conditions as those imposed by obesity and insulin resistance. Our data reveal a novel role for HMGB1 as a stimulatory factor of insulin secretion of ß-pancreatic cells.
Autores:
Naukkarinen ; Heinonen; Hakkarainen; et al.
Revista:
DIABETOLOGIA
ISSN:
0012-186X
Año:
2014
Vol.:
57
N°:
1
Págs.:
167-176
Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2014
Vol.:
99
N°:
10
Págs.:
e2004-e2009
We conclude that serum betatrophin is decreased in human obesity, being further reduced in obesity-associated insulin resistance. Betatrophin levels are closely related to obesity-associated cardiometabolic risk factors, emerging as a potential biomarker of insulin resistance and T2D.
Revista:
SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES
ISSN:
0930-2794
Año:
2014
Vol.:
28
N°:
2
Págs.:
2412 - 2420
Background
Bariatric surgery (BS) has proven to be an effective treatment for morbid obesity. Osteopontin (OPN) is a proinflammatory cytokine involved in the development of obesity. The aim of our study was to determine the effect of weight loss following BS on circulating levels of OPN in humans.
Methods
Body composition and circulating concentrations of OPN and markers of bone metabolism were determined in obese patients who underwent Roux-en-Y gastric bypass (RYGB; n = 40) or sleeve gastrectomy (SG; n = 11).
Results
Patients who underwent RYGB or SG showed decreased body weight (P < 0.001) and body fat percentage (P < 0.001) as well as lower insulin resistance. However, plasma OPN levels were significantly increased after RYGB (P < 0.001) but remained unchanged following SG (P = 0.152). Patients who underwent RYGB also showed significantly increased C-terminal telopeptide of type-I collagen (ICTP) (P < 0.01) and osteocalcin (P < 0.001) while bone mineral density tended to decrease (P = 0.086). Moreover, OPN concentrations were positively correlated with the bone resorption marker ICTP after surgery. On the other hand, patients who underwent SG showed significantly increased ICTP levels (P < 0.05), and the change in OPN was positively correlated with the change in ICTP and negatively with the change in vitamin D after surgery (P < 0.05).
Conclusions
RYGB increased circulating OPN levels, while they remained unaltered after SG. The increase in OPN levels after RYGB could be related to the increased bone resorption in relation to its well-known effects on bone of this malabsorptive procedure in comparison to the merely restrictive SG.
Revista:
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
ISSN:
0925-4439
Año:
2014
Vol.:
1842
N°:
12 Pt A
Págs.:
2448 - 2456
G protein-coupled receptor kinase 2 (GRK2) has recently emerged as a negative modulator of insulin signaling. GRK2 downregulation improves insulin sensitivity and prevents systemic insulin resistance. Cardiac GRK2 levels are increased in human heart failure, while genetically inhibiting GRK2 leads to cardioprotection in mice. However, the molecular basis underlying the deleterious effects of GRK2 up-regulation and the beneficial effects of its inhibition in the heart are not fully understood. Therefore, we have explored the interconnections among a systemic insulin resistant status, GRK2 dosage and cardiac insulin sensitivity in adult (9 month-old) animals. GRK2(+/-) mice display enhanced cardiac insulin sensitivity and mild heart hypertrophy with preserved systolic function. Cardiac gene expression is reprogrammed in these animals, with increased expression of genes related to physiological hypertrophy, while the expression of genes related to pathological hypertrophy or to diabetes/obesity co-morbidities is repressed. Notably, we find that cardiac GRK2 levels increase in situations where insulin resistance develops, such as in ob/ob mice or after high fat diet feeding. Our data suggest that GRK2 downregulation/inhibition can help maintain cardiac function in the face of co-morbidities such as insulin resistance, diabetes or obesity by sustaining insulin sensitivity and promoting a gene expression reprogramming that confers cardioprotection.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2014
Vol.:
24
Págs.:
1702-1708
Circulating OPN levels decreased with HFD feeding remaining unaltered after SG. The expression of Spp1 in EWAT and liver was not modified by SG. The global improvement of metabolism after SG appears not to involve changes in serum OPN concentrations as well as in EWAT and liver expression in rats.
Revista:
DIABETES CARE
ISSN:
0149-5992
Año:
2014
Vol.:
37
N°:
10
Págs.:
2813-2821
The current study provides evidence for the existence of a comparable adverse cardiometabolic profile in MHO and MAO patients; thus the MHO concept should be applied with caution. A better identification of the obesity phenotypes and a more precise diagnosis are needed for improving the management of obese individuals.
Autores:
Moreno-Navarrete, JM; Novelle, MG; Catalán, V; et al.
Revista:
DIABETES CARE
ISSN:
0149-5992
Año:
2014
Vol.:
37
N°:
4
Págs.:
1092-100
Circulating markers of iron overload are associated with insulin resistance. Less is known about the impact of iron overload on adipose tissue (AT). We hypothesized that gene expression markers of iron metabolism in AT could be associated with insulin action. RESEARCH DESIGN AND METHODS The AT expression of ferroportin (SLC40A1), transferrin (TF), TF receptor (TFRC), ferritin (FT) heavy polypeptide 1 (FTH1), and FT light polypeptide (FTL) was analyzed cross-sectionally in three independent cohorts and also after weight loss-induced changes in insulin sensitivity (clamp M value) in an independent fourth cohort. RESULTS In human AT, TF mRNA and protein levels were decreased with obesity and insulin resistance in the three cohorts and were positively associated with adipogenic mRNAs and insulin action. Otherwise, FTL mRNA and protein and SLC40A1 transcripts were positively associated with BMI and negatively linked to adipogenic genes and insulin action. Bariatric surgery-induced weight loss led to increased TF and decreased TFRC, FTH1, FTL, and SLC40A1 in subcutaneous AT in parallel to improved insulin action. CONCLUSIONS These results suggest that iron overload impacts on AT in association with insulin resistance.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2014
Vol.:
9
N°:
5
Págs.:
e98398
Osteopontin (OPN) is a multifunctional extracellular matrix (ECM) protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD) using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT) and liver in wild type (WT) mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2014
Vol.:
38
N°:
9
Págs.:
1213 - 1220
Background/Objectives:Glycerol represents an important metabolite for the control of lipid accumulation and hepatic gluconeogenesis. We investigated whether hepatic expression and functionality of aquaporin-9 (AQP9), a channel mediating glycerol influx into hepatocytes, is impaired in non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) in the context of insulin resistance.Subjects/Methods:Liver biopsies were obtained from 66 morbid obese patients undergoing bariatric surgery (66% women, mean body mass index (BMI) 46.1±1.0 kg m-2) with available liver echography and pathology analysis of the biopsies in this cross-sectional study. Subjects were classified according to normoglycemia (NG), impaired glucose tolerance (IGT) or type 2 diabetes (T2D). Hepatic expression of AQP9 was analyzed by real-time PCR, western blotting and immunohistochemistry, while glycerol permeability (P gly) was measured by stopped-flow light scattering.Results:AQP9 was the most abundantly (P<0.0001) expressed aquaglyceroporin in human liver (AQP9>>>AQP3>AQP7>AQP10). Obese patients with T2D showed increased plasma glycerol as well as lower P gly and hepatic AQP9 expression. The prevalence of NAFLD and NASH in T2D patients was 100 and 65%, respectively. Interestingly, AQP9 expression was decreased in patients with NAFLD and NASH as compared with those without hepatosteatosis, in direct relation to the degree of steatosis and lobular inflammation, being further reduced in insulin-resistant individuals. The association of AQP9 with insulin sensitivity was independent of BMI and age. Consistent with these data, fasting insulin and C-reactive protein contributed independently to 33.1% of the hepatic AQP9 mRNA expression variance after controlling for the effects of age and BMI.Conclusions:AQP9 downregulation together with the subsequent reduction in hepatic glycerol permeability in insulin-resistant states emerges as a compensatory mechanism whereby the liver counteracts further triacylglycerol accumulation within its parenchyma as well as reduces hepatic gluconeogenesis in patients with NAFLD.
Revista:
SURGERY FOR OBESITY AND RELATED DISEASES
ISSN:
1550-7289
Año:
2013
Vol.:
9
N°:
2
Págs.:
306-314
The increased levels of chemerin in obesity and its positive association with inflammation suggest a role for this chemoattractant protein in the changes that take place in visceral adipose tissue in the presence of energy surplus, establishing a link between inflammation and the greater risk of the development of metabolic disease.
Autores:
Gena; Mastrodonato; Portincasa; et al.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2013
Vol.:
8
N°:
10
Págs.:
e78139
One form of liver steatosis, namely Non-Alcoholic Fatty Liver Disease (NAFLD), is a worrisome health problem worldwide characterized by intrahepatic triacylglycerol (TG) overaccumulation. NAFLD is a common feature of metabolic syndrome being often associated with obesity, dyslipidemia and diabetes and mostly closely linked to insulin resistance. The mechanism of NAFLD pathogenesis is object of intense investigation especially regarding complex systems ultimately resulting in excessive TG deposition in hepatocytes. However, scarce is the attention about the relevance of hepatic import of glycerol, the other primary source (as glycerol-3-phosphate) of increased TG in hepatocytes. Obese leptin-deficient (ob/ob) mice, an animal model of NAFLD, were used to evaluate the functional involvement of Aquaporin-9 (AQP9), the major pathway of liver glycerol entry, in hepatosteatosis. By RT-PCR and qPCR, the level of Aqp9 mRNA in the liver of starved obese mice was comparable with the corresponding control lean littermates. By immunoblotting, the AQP9 protein at the hepatocyte sinusoidal plasma membrane of obese mice was markedly lower (33%) than lean mice, a finding fully confirmed by immunohistochemistry. By stopped-flow light scattering, the liver glycerol permeability of ob/ob mice was significantly lower (53%) than lean mice, a finding consistent with both the observed down-regulation of AQP9 protein and increased level of plasma glycerol characterizing obese mice. In summary, our re
Autores:
Moreno-Navarrete, JM; Touskova, V; Sabater, M; et al.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2013
Vol.:
37
N°:
9
Págs.:
1230-37
Liver, but not adipose tissue, might be the source of increased circulating PEDF linked to insulin resistance.
Revista:
JOURNAL OF CLINICAL SLEEP MEDICINE
ISSN:
1550-9389
Año:
2013
Vol.:
9
N°:
11
Págs.:
1165 - 1171
Objective: To evaluate the relation between obstructive sleep apnea (OSA) and left ventricular mass (LVM) in morbid obesity and the influence of gender, menopausal status, anthropometry, body composition, hypertension, and other cardiovascular risk factors in this relationship.
Design: Cross-sectional descriptive study.
Methods: Polysomnographic and echocardiographic studies were performed in a cohort of 242 patients (86 men, 100 premenopausal (PreM) and 56 postmenopausal (PostM) women), with grade II obesity and above (BMI: 43.7 ± 0.4 kg/m(2)) to investigate OSA and LVM respectively. Anthropometry, body composition, glucose tolerance, and blood pressure were also recorded.
Results: OSA to different degrees was diagnosed in 76.2% of the patients (n: 166), its prevalence being 90.9% (n: 70) for men, and 76% (n: 38) and 63.8% (n: 58) for PostM and PreM women, respectively (p < 0.01). LVM excess was greatest for PostM women (90.2%), followed by men (81.9%) and PreM females (69.6%) (p < 0.01). LVM values increased in accordance to OSA severity (absence, 193.7 ± 6.9 g; mild, 192.6 ± 7.8 g; moderate, 240.5 ± 12.5 g; severe, 273.6 ± 14.6 g; p < 0.01). LVM magnitude correlated with the menopausal state, age, central adiposity, hypertension (HT), type 2 diabetes (DM), desaturation index (DI), and apnea-hypopnea index (AHI) (r = 0.41; p < 0.01). The relationship between LVM and AHI persisted in the multivariate analysis (ß = 0.25; p < 0.05) after adjusting for age, gender, menopausal state, BMI, waist circumference, neck circumference, DI, fasting plasma glucose, DM, and HT. But if tobacco habits are included, the statistical difference disappears (ß = 0.22; p = 0.06).
Conclusions: Morbid obesity is frequently associated with abnormal LVM, particularly in patients with OSA; this association is independent of HT, BMI, body composition, and other clinical factors, supporting a direct role of OSA on LVM in morbid obesity. This suggests that OSA and LVM might be taken as predictors of the cardiovascular risk in these patients.
Revista:
EUROPEAN JOURNAL OF NUTRITION
ISSN:
1436-6207
Año:
2013
Vol.:
52
N°:
6
Págs.:
1587-1595
These findings represent the first observation that STEAP4 and NGAL mRNA and protein levels in human VAT are related to iron status. Moreover, STEAP4 and NGAL are associated with pro-inflammatory markers suggesting their potential involvement in the low-grade chronic inflammation accompanying obesity.
Autores:
Ortega, F; Mercader, JM; Catalán, V; et al.
Revista:
CLINICAL CHEMISTRY
ISSN:
0009-9147
Año:
2013
Vol.:
59
N°:
5
Págs.:
781-92
Circulating miRNAs are deregulated in severe obesity. Weight loss-induced changes in this profile and the study of in silico targets support this observation and suggest a potential mechanistic relevanc
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2012
Vol.:
36
N°:
2
Págs.:
286 - 294
Autores:
Ortega, F. J.; Moreno-Navarrete, J. M.; Mayas, D.; et al.
Revista:
PLOS ONE
ISSN:
1932-6203
Context: Expression and activity of the main lipogenic enzymes is paradoxically decreased in obesity, but the mechanisms behind these findings are poorly known. Breast Cancer 1 (BrCa1) interacts with acetyl-CoA carboxylase (ACC) reducing the rate of fatty acid biosynthesis. In this study, we aimed to evaluate BrCa1 in human adipose tissue according to obesity and insulin resistance, and in vitro cultured adipocytes. Research Design and Methods: BrCa1 gene expression, total and phosphorylated (P-) BrCa1, and ACC were analyzed in adipose tissue samples obtained from a total sample of 133 subjects. BrCa1 expression was also evaluated during in vitro differentiation of human adipocytes and 3T3-L1 cells. Results: BrCa1 gene expression was significantly up-regulated in both omental (OM; 1.36-fold, p = 0.002) and subcutaneous (SC; 1.49-fold, p = 0.001) adipose tissue from obese subjects. In parallel with increased BrCa1 mRNA, P-ACC was also up-regulated in SC (p = 0.007) as well as in OM (p = 0.010) fat from obese subjects. Consistent with its role limiting fatty acid biosynthesis, both BrCa1 mRNA (3.5-fold, p<0.0001) and protein (1.2-fold, p = 0.001) were increased in pre-adipocytes, and decreased during in vitro adipogenesis, while P-ACC decreased during differentiation of human adipocytes (p = 0.005) allowing lipid biosynthesis. Interestingly, BrCa1 gene expression in mature adipocytes was restored by inflammatory stimuli (macrophage conditioned medium), whereas lipogenic genes significantly decreased. Conclusions: The specular findings of BrCa1 and lipogenic enzymes in adipose tissue and adipocytes reported here suggest that BrCa1 might help to control fatty acid biosynthesis in adipocytes and adipose tissue from obese subjects.
Revista:
DIABETES CARE
ISSN:
0149-5992
Año:
2012
Vol.:
35
N°:
2
Págs.:
383-88
CUN-BAE is an easy-to-apply predictive equation that may be used as a first screening tool in clinical practice. Furthermore, our equation may be a good tool for identifying patients at cardiovascular and type 2 diabetes risk.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2012
Vol.:
22
N°:
11
Págs.:
1786 - 1787
Autores:
Fagundo, A. B.; De La Torre, R.; Jimenez-Murcia, S.; et al.
Revista:
PLOS ONE
ISSN:
1932-6203
Background: Extreme weight conditions (EWC) groups along a continuum may share some biological risk factors and intermediate neurocognitive phenotypes. A core cognitive trait in EWC appears to be executive dysfunction, with a focus on decision making, response inhibition and cognitive flexibility. Differences between individuals in these areas are likely to contribute to the differences in vulnerability to EWC. The aim of the study was to investigate whether there is a common pattern of executive dysfunction in EWC while comparing anorexia nervosa patients (AN), obese subjects (OB) and healthy eating/weight controls (HC). Methods: Thirty five AN patients, fifty two OB and one hundred thirty seven HC were compared using the Wisconsin Card Sorting Test (WCST); Stroop Color and Word Test (SCWT); and Iowa Gambling Task (IGT). All participants were female, aged between 18 and 60 years. Results: There was a significant difference in IGT score (F(1.79); p<.001), with AN and OB groups showing the poorest performance compared to HC. On the WCST, AN and OB made significantly more errors than controls (F(25.73); p<.001), and had significantly fewer correct responses (F(2.71); p<.001). Post hoc analysis revealed that the two clinical groups were not significantly different from each other. Finally, OB showed a significant reduced performance in the inhibition response measured with the Stroop test (F(5.11); p<.001) compared with both AN and HC. Conclusions: These findings suggest that EWC subjects (namely AN and OB) have similar dysfunctional executive profile that may play a role in the development and maintenance of such disorders.
Revista:
ENDOSCOPY
ISSN:
0013-726X
Año:
2012
Vol.:
44
N°:
Suppl. 2
Págs.:
UCTN:E366-7
Revista:
LIVER INTERNATIONAL
ISSN:
1478-3223
Año:
2012
Vol.:
32
N°:
6
Págs.:
951-61
The results suggest alterations in mitochondrial function and methionine metabolism as potential contributing factors to increased oxidative stress in liver of obese diabetic patients which may be influencing the development of NAFLD and NASH.
Revista:
Journal of Clinical Endocrinology & Obesity
ISSN:
0021-972X
Año:
2012
Vol.:
97
N°:
10
Págs.:
e1880 - e1889
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2012
Vol.:
7
N°:
1
Págs.:
e29389
Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P¿=¿0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P<0.001) and Tbc1d4 (P¿=¿0.004) in the leptin-treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P¿=¿0.015 and P¿=¿0.023, respectively) and pair-fed ob/ob (P¿=¿0.036 and P¿=¿0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P¿=¿0.013) and pair-fed ob/ob (P¿=¿0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4.
Autores:
Ribeiro, R; Monteiro, C; Catalán, V; et al.
Revista:
BMC MEDICINE
ISSN:
1741-7015
Año:
2012
Vol.:
10
Págs.:
108
Obesity and excess adiposity modified the expression of PP adipose tissue genes to ultimately foster fat mass growth. In patients with prostate cancer the expression profile of PP adipose tissue accounted for hypercellularity and reduced immunosurveillance. Both findings may be liable to promote a favorable environment for prostate cancer progression.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2012
Vol.:
22
N°:
4
Págs.:
634 - 640
Background: Sleeve gastrectomy (SG) has been used as a multipurpose surgical procedure for the treatment of morbid obesity. The aim of the study was to analyze gastric morphology and histology at two different time points after SG in rats. Methods: Thirty-five male Wistar rats were fed ad libitum during 3 months on a high-fat diet to induce obesity. Subsequently, 25 diet-induced obese rats underwent either SG (n=12) or a sham operation (n=13). The remaining ten obese animals encompassed the nonoperated control group (Co). Four weeks postoperatively, 15 rats (n05 rats/experimental group) were sacrificed, while the remaining 20 rats were sacrificed after 16 weeks (animals/group; Co=5, sham=8, SG=7) to compare the gastric morphological and histopathological changes over time. Body weight and food intake were regularly recorded. Results: For both time periods, the Co groups exhibited the highest body weight, while the rats undergoing the SG showed the lowest weight gain (P<0.05). Initially, significant differences (P<0.005) in food intake relative to body weight were observed between the Co rats and animals undergoing surgery, which disappeared thereafter. The actual total stomach sizeafter both experimental periods in the SG group was similar to that of non- and sham-operated rats mainly due to a forestomach enlargement, which was more pronounced after 16 weeks. Traits of gastritis cystica profunda characterized by gastric foveolae elongation with hyperplasia and cystic dilatation of the glandswere observed in the residual stomachs of the sleeve-gastrectomized rats. These findings were mostly observed after 16 weeks of performing the SG, although they were also detected occasionally following 4 weeks postoperatively. No intestinal metaplasia was observed. Conclusion: After SG gastric macro- and microscopic changes with functional implications in both the short and long term take place.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2012
Vol.:
22
N°:
9
Págs.:
1481 - 1490
Sleeve gastrectomy constitutes an effective surgical procedure for the treatment of morbid obesity. The aim of the present study was to establish the effects of sleeve gastrectomy and caloric restriction on weight loss and cardiovascular parameters in diet-induced obese (DIO) rats.
Male Wistar DIO rats were subjected to surgical interventions (n = 30) (sham operation, sleeve gastrectomy, or pair-fed to the amount of food eaten by sleeve-gastrectomized animals and compared to lean control rats) or dietary interventions (n = 40) (fed ad libitum a normal diet (ND) or a high-fat diet or an ND with a caloric restriction of 25 %). Systolic blood pressure (SBP), diastolic blood pressure, and mean blood pressure values and heart rate (HR) were recorded in conscious, resting animals by noninvasive tail-cuff plethysmography before and 3 weeks after surgical or dietary interventions.
Both sleeve gastrectomy and caloric restriction induced a reduction in body weight, whole-body adiposity, and serum leptin together with an increased excess weight loss in DIO rats. Sleeve gastrectomy was further associated with an improvement in insulin resistance and the lipid profile, as well as with a reduction in serum ghrelin levels. A decrease in HR and heart weight was observed in caloric-restricted groups. Sleeve-gastrectomized rats not only exhibited a reduction in HR (a dagger HR = -45 +/- 19 bpm) but also in SBP values (a dagger SBP = -22 +/- 10 mmHg) compared to the DIO rats (a dagger SBP = 14 +/- 8 mmHg).
Our findings provide evidence that the beneficial effects of sleeve gastrectomy on blood pressure values are beyond weight loss in rats with diet-induced obesity.
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2012
Vol.:
22
N°:
2
Págs.:
309-315
Sleeve gastrectomy constitutes an effective surgical procedure for the treatment of morbid obesity in humans and rodents with diet-induced obesity. The aim of the present study was to establish the effects of sleeve gastrectomy on weight loss and cardiovascular parameters in genetically obese (fa/fa) Zucker rats.
Eleven-week-old male obese (fa/fa) (n = 20) Zucker rats were assigned to three alternative procedures (sham operation, sleeve gastrectomy, or pair-fed to the amount of food eaten by sleeve-gastrectomized animals) and compared with lean Zucker (Fa/Fa) rats (n = 9). Systolic (SBP), diastolic (DBP), and mean (MBP) blood pressure values as well as heart rate (HR) were recorded in conscious, resting animals by non-invasive tail-cuff plethysmography before and 3 weeks after the surgical interventions.
Sleeve-gastrectomized rats experienced a reduction in body weight (P < 0.01), total adiposity amounts (P < 0.001), together with an increased excess weight loss (%EWL) (P < 0.05) compared with sham-operated and pair-fed animals 3 weeks after the surgical interventions. Rats with sleeve gastrectomy exhibited reduced (P < 0.01) blood pressure values (Delta SBP = -11 +/- 8 mmHg; Delta DBP = -6 +/- 4 mmHg; Delta MBP = -8 +/- 6 mmHg) compared with the control group, but no changes were observed in HR (P = 0.560). Sham-operated and pair-fed groups did not alter their cardiovascular variables.
Our findings provide evidence of the beneficial effects of sleeve gastrectomy on blood pressure values in addition to the weight loss in obese (fa/fa) Zucker rats independently of surgical trauma and food intake reduction.
Autores:
Moreno-Navarrete, JM; Catalán, V; White, L; et al.
Revista:
DIABETES
ISSN:
0012-1797
Año:
2012
Vol.:
61
N°:
2
Págs.:
281-91
GPR55 is a putative cannabinoid receptor, and l-¿-lysophosphatidylinositol (LPI) is its only known endogenous ligand. We investigated 1) whether GPR55 is expressed in fat and liver; 2) the correlation of both GPR55 and LPI with several metabolic parameters; and 3) the actions of LPI on human adipocytes. We analyzed CB1, CB2, and GPR55 gene expression and circulating LPI levels in two independent cohorts of obese and lean subjects, with both normal or impaired glucose tolerance and type 2 diabetes. Ex vivo experiments were used to measure intracellular calcium and lipid accumulation. GPR55 levels were augmented in the adipose tissue of obese subjects and further so in obese patients with type 2 diabetes when compared with nonobese subjects. Visceral adipose tissue GPR55 correlated positively with weight, BMI, and percent fat mass, particularly in women. Hepatic GPR55 gene expression was similar in obese and type 2 diabetic subjects. Circulating LPI levels were increased in obese patients and correlated with fat percentage and BMI in women. LPI increased the expression of lipogenic genes in visceral adipose tissue explants and intracellular calcium in differentiated visceral adipocytes. These findings indicate that the LPI/GPR55 system is positively associated with obesity in humans
Revista:
Diabetologia
ISSN:
0012-186X
Año:
2012
Vol.:
55
N°:
11
Págs.:
3038 - 3050
Revista:
PHYSIOLOGICAL GENOMICS (ONLINE)
ISSN:
1531-2267
Año:
2012
Vol.:
44
N°:
13
Págs.:
678-688
Leptin and nitric oxide (NO) are implicated in the control of energy homeostasis. The aim of the present study was to examine the impact of the absence of the inducible NO synthase (iNOS) gene on the regulation of energy balance in ob/ob mice analyzing the changes in gene expression levels in brown adipose tissue (BAT). Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated and the expression of genes involved in energy balance including fatty acid and glucose metabolism as well as mitochondrial genes were analyzed by microarrays. DBKO mice exhibited an improvement in energy balance with a decrease in body weight
(P < 0.001), total fat pads (P < 0.05) and food intake (P < 0.05) as well as an enhancement in BAT function as compared to ob/ob mice. To better understand the molecular events associated with this improvement, BAT gene expression was analyzed. Of particular interest, gene expression levels of the key subunit of the Mediator complex Med1 was upregulated (P < 0.05) in DBKO mice. Real-Time PCR and immunohistochemistry further confirmed this data. Med1 is implicated in adipogenesis, lipid metabolic and biosynthetic processes, glucose metabolism and mitochondrial metabolic pathways. Med1 plays an important role in the transcriptional control of genes implicated in energy homeostasis, suggesting that the improvement in energy balance and BAT function of the DBKO mice is mediated, at least in part, through the transcription coactivator Med1.
Revista:
NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES
ISSN:
0939-4753
Año:
2011
Vol.:
21
N°:
4
Págs.:
245 - 253
Our work shows that NAMPT circulating concentrations and mRNA expression levels in PBC are increased in obese patients and that plasma NAMPT levels are related to inflammation, lipid metabolism and hepatic enzymes suggesting a potential involvement in fatty liver disease and in the obesity-associated inflammatory state.
Revista:
DIABETES & METABOLIC SYNDROME
ISSN:
1878-0334
Año:
2011
Vol.:
5
N°:
2
Págs.:
66 - 70
INTRODUCTION: Factors leading to weight loss and weight stabilization after bariatric surgery are not fully understood. Our aim was to evaluate, in Sprague-Dawley rats, the histological and gut hormonal changes after Larrad-biliopancreatic diversion (Larrad-BPD).
MATERIALS AND METHODS: Rats randomly underwent the following protocols: Larrad-BPD (n=4) versus pair fed (PF) (n=4). Weight and food intake were measured every day. By immunohistochemistry ghrelin was examined in the stomach, while cholecystokinin (CCK), glucagon-like-peptide-1 (GLP-1), peptide YY (PYY) and serotonin (5-HT) expression were analyzed in alimentary limb and ileum following or not the Larrad-BPD.
RESULTS: Larrad-BPD rats exhibited significant (P<0.05) weight loss compared to PF rats. Villi enlongation was observed in Larrad-BPD rats. In residual stomach, ghrelin was diminished. In the alimentary limb, ghrelin and CCK positive cells were detected more than in the ileum of PF rats. GLP-1 expression was decreased and PYY expression was absent after Larrad-BPD compared with PF rats.
DISCUSSION: Larrad-BPD is followed by histological changes and a pleiotropic gut endocrine response aimed to compensate the reduction of intestinal area exposed to food. Until now, the hormones responsible for the intestinal hypertrophy have not been defined.
Revista:
OBESITY
ISSN:
1930-7381
Año:
2011
Vol.:
19
N°:
7
Págs.:
1439 - 1444
Autores:
Ortega, FJ; Moreno-Navarrete, JM; Sabater, M; et al.
Revista:
EUROPEAN JOURNAL OF ENDOCRINOLOGY
ISSN:
0804-4643
Año:
2011
Vol.:
165
N°:
4
Págs.:
639 - 645
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2011
Vol.:
96
N°:
1
Págs.:
200 - 209
Revista:
MOLECULAR MEDICINE
ISSN:
1076-1551
Año:
2011
Vol.:
17
N°:
11-12
Págs.:
1157-67
Calprotectin has been recently described as a novel marker of obesity. The aim of this study was to determine the circulating concentrations and expression levels of calprotectin subunits (S100A8 and S100A9) in visceral adipose tissue (VAT), exploring its impact on insulin resistance and inflammation and the effect of weight loss. We included 53 subjects in the study. Gene expression levels of the S100A8/A9 complex were analyzed in VAT as well as in both adipocytes and stromovascular fraction cells (SVFCs). In addition, circulating calprotectin and soluble receptor for the advanced glycation end product (sRAGE) concentrations were measured before and after weight loss achieved by Roux-en-Y gastric bypass (RYGB) (n = 26). Circulating concentrations and VAT expression of S100A8/A9 complex were increased in normoglycemic and type 2 diabetic obese patients (P < 0.01) and associated with markers of inflammation (P < 0.01). Oppositely, concentrations of sRAGE were significantly lower (P < 0.001) in both obese groups compared to lean volunteers. Elevated calprotectin levels in obese patients decreased (P < 0.00001) after RYGB, whereas sRAGE concentrations tended to increase. Calprotectin was mainly expressed by SVFCs, and its expression was significantly correlated (P < 0.01) with mRNA levels of the monocyte-macrophage-related molecules macrophage-specific antigen CD68 (CD68), monocyte chemotactic protein 1 (MCP1), integrin ¿-M (CD11B), and NADPH oxidase 2 (NOX2). Tumor necrosis fac
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2011
Vol.:
96
N°:
4
Págs.:
586 - 597
Revista:
ANALES DEL SISTEMA SANITARIO DE NAVARRA
ISSN:
1137-6627
Año:
2011
Vol.:
34
N°:
2
Págs.:
141 - 144
Autores:
Pulido, MR; Díez-Ruiz, A; Jiménez-Gómez, Y; et al.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2011
Vol.:
6
N°:
7
Págs.:
e22931
Revista:
OBESITY SURGERY
ISSN:
0960-8923
Año:
2011
Vol.:
21
N°:
9
Págs.:
1438 - 1443
Background: Sleeve gastrectomy (SG) has been used for the surgical treatment of morbid obesity as a first or definitive procedure with satisfactory results. The objective of this study in rats was to establish the effects of SG on weight loss depending on the post-surgical type of diet followed. Methods: Thirty male Wistar rats were fed ad libitum during 3 months on a high-fat diet (HFD) to induce obesity. After this first phase, rats were subdivided in three groups of ten rats each and underwent a sham intervention, an SG, or no surgery but were pair-fed to the amount of food eaten by the animals of the SG group. At this time point, half of the animals in each group continued to be fed on the HFD, while the other half was switched to a normal chow diet (ND). Thus, the following subgroups were established: sham-ND, sleeve-ND, pair-fed-ND as well as sham-HFD, sleeve-HFD, and pair-fed-HFD. Body weight and food intake were recorded daily for 4 weeks. The feed efficiency rate (FER) was determined from weekly weight gains and caloric consumption during this period. Results: Statistically significant (P¿<¿0.05) differences in body weight were observed between the six experimental groups after 4 weeks of the interventions with rats in the sleeve-ND group experimenting the highest weight loss (-78.2¿±¿10.3 g) and animals in the pair-fed-HFD group exhibiting the lowest weight reduction (-4.0¿±¿0.1 g). Interestingly, the FER value of rats that underwent the SG and continued to be fed on a HFD was significantly (P¿<¿0.05) lower than that of sham operated and pair-fed animals on the same diet. Conclusion: The positive effects of SG on weight reduction are observed in obese rats submitted to the intervention and subsequently following an ND or even an HFD.
Revista:
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
ISSN:
0955-2863
Año:
2011
Vol.:
22
N°:
7
Págs.:
634 - 641
Revista:
Journal of hypertension
ISSN:
0263-6352
Año:
2010
Vol.:
28
N°:
3
Págs.:
560 - 567
Objective The gut-derived hormone, ghrelin, improves cardiac function in healthy individuals and patients with chronic heart failure. The aim of this study was to investigate whether the major isoforms of the hormone, acylated and desacyl ghrelin, are related to inappropriate left ventricular mass in patients with the metabolic syndrome (MetS).
Methods and results Plasma concentrations of ghrelin forms were measured in 180 white participants (65 normal weight, 60 obese without MetS and 55 obese with MetS; 56% men). MetS was defined according to Adult Treatment Panel III criteria. The presence of left ventricular hypertrophy (LVH) was diagnosed by sex-specific left ventricular mass/height(2.7) cut-off values (> 49.2 g/m(2.7) for men and > 46.7 g/m(2.7) for women). Circulating concentrations of acylated ghrelin were increased in obesity and MetS, whereas desacyl ghrelin levels were decreased. Compared with participants in the lowest tertiles, the age-adjusted and sex-adjusted odds of having MetS were lower in the highest category of desacyl ghrelin (odds ratio 0.1, 95% confidence interval 0.1-0.4, P < 0.001). The prevalence of LVH was increased in the highest tertile of acylated ghrelin (odds ratio 3.4, 95% confidence interval 1.7-5.6, P < 0.05). Plasma acylated ghrelin was increased (P < 0.05) in patients with MetS exhibiting LVH compared with those with appropriate left ventricular mass, whereas plasma desacyl ghrelin was not changed (P = 0.490).
Conclusion Acylated ghrelin was positively associated with SBP and left ventricular mass indices, even after correction for BMI. These results suggest that the increased acylated ghrelin concentrations may represent a compensatory mechanism to overcome the development of hypertension and LVH in patients with MetS.
Autores:
Moreno-Navarrete, JM; Catalán, V; Ortega, F; et al.
Revista:
NUTRITION AND METABOLISM
ISSN:
1743-7075
Autores:
Fernández-Real, JM; Ortega, F; Gómez-Ambrosi, J; et al.
Revista:
OSTEOPOROSIS INTERNATIONAL
ISSN:
0937-941X
Año:
2010
Vol.:
21
N°:
12
Págs.:
2101 - 2107
Autores:
Sabater, M; Moreno-Navarrete, JM; Ortega, FJ; et al.
Revista:
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
ISSN:
0021-972X
Año:
2010
Vol.:
95
N°:
10
Págs.:
4720 - 4728
Autores:
Moreno-Navarrete, JM; Martínez-Barricarte, R; Catalán, V; et al.
Revista:
DIABETES
ISSN:
0012-1797
Año:
2010
Vol.:
59
N°:
1
Págs.:
200 - 209
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2010
Vol.:
5
N°:
6
Págs.:
e10962
BACKGROUND:
Leptin and nitric oxide (NO) on their own participate in the control of non-shivering thermogenesis. However, the functional interplay between both factors in this process has not been explored so far. Therefore, the aim of the present study was to analyze the impact of the absence of the inducible NO synthase (iNOS) gene in the regulation of energy balance in ob/ob mice.
METHODS AND FINDINGS:
Double knockout (DBKO) mice simultaneously lacking the ob and iNOS genes were generated, and the expression of molecules involved in the control of brown fat cell function was analyzed by real-time PCR, western-blot and immunohistochemistry. Twelve week-old DBKO mice exhibited reduced body weight (p<0.05), decreased amounts of total fat pads (p<0.05), lower food efficiency rates (p<0.05) and higher rectal temperature (p<0.05) than ob/ob mice. Ablation of iNOS also improved the carbohydrate and lipid metabolism of ob/ob mice. DBKO showed a marked reduction in the size of brown adipocytes compared to ob/ob mutants. In this sense, in comparison to ob/ob mice, DBKO rodents showed an increase in the expression of PR domain containing 16 (Prdm16), a transcriptional regulator of brown adipogenesis. Moreover, iNOS deletion enhanced the expression of mitochondria-related proteins, such as peroxisome proliferator-activated receptor gamma coactivator-1 alpha (Pgc-1alpha), sirtuin-1 (Sirt-1) and sirtuin-3 (Sirt-3). Accordingly, mitochondrial uncoupling proteins 1 and 3 (Ucp-1 and Ucp-3) were upregulated in brown adipose tissue (BAT) of DBKO mice as compared to ob/ob rodents.
CONCLUSION:
Ablation of iNOS improved the energy balance of ob/ob mice by decreasing food efficiency through an increase in thermogenesis. These effects may be mediated, in part, through the recovery of the BAT phenotype and brown fat cell function improvement.
Autores:
Laguna, S; Príncipe, RM; Botella, S; et al.
Revista:
AVANCES EN DIABETOLOGIA
ISSN:
1134-3230
Año:
2010
Vol.:
26
N°:
3
Págs.:
173 - 177
Autores:
Fernandez-Real, JM.; Menendez, JA.; Moreno-Navarrete, JM.; et al.
Revista:
DIABETES
ISSN:
0012-1797
Año:
2010
Vol.:
59
N°:
6
Págs.:
1506 - 11
Our results suggest that circulating FASN is a biomarker of overnutrition-induced insulin resistance that could provide diagnostic and prognostic advantages by providing insights on the individualized metabolic stress.
Autores:
Hurtado del Pozo, C; Calvo, RM; Vesperinas-García, G.; et al.
Revista:
OBESITY
ISSN:
1930-7381
Año:
2010
Vol.:
18
N°:
5
Págs.:
897 - 903
Housekeeping genes frequently used in gene expression studies are highly regulated in human adipose tissue. To ensure a correct interpretation of results, it is critical to select appropriate reference genes. Subcutaneous (SC) and omental (OM) adipose tissue expression was analyzed from lean and obese subjects using whole genome complementary DNA (cDNA) microarrays to identify stably expressed genes and commercial TaqMan low density arrays (LDAs), with 16 common control genes. The best candidate gene from microarrays analysis was F-box and leucine-rich repeat protein-10 (FBXL10) (fold-change 10(-3) P < 0.01), an ubiquitous nucleolar protein evolutionarily conserved. Hypoxanthine phosphoribosyltransferase 1 (HPRT1) and importin 8 (IPO8), were the best reference genes among the 16 genes in the LDAs with coefficient of variation (CV) of 4.51 and 4.55%, respectively. However, when the LDAs data were further analyzed by the geNorm and NormFinder softwares, IPO8, a nuclear protein mediating import of proteins, was the first and the third better reference gene, respectively. IPO8 and FBXL10 were further validated by real-time PCR in additional OM and SC fat samples and primary cultured preadipocytes. According to their CV, IPO8 resulted more suitable than FBXL10 in both adipose tissue depots and SC preadipocytes, whereas FBXL10 performed better than IPO8 in OM cultured preadipocytes. Both genes expression levels did not change throughout adipogenesis. Thus, we provide clear evidence that IPO8 and FBXL10 are good candidates to use as reference genes in gene expression studies in human OM and SC adipose tissues as well as differentiated primary preadipocytes
Autores:
Poulain-Godefroy, O; Le Bacquer, O; Plancq, P; et al.
Revista:
MEDIATORS OF INFLAMMATION
ISSN:
0962-9351
Año:
2010
Vol.:
2010
Págs.:
823486
Revista:
JOURNAL OF NUTRITIONAL BIOCHEMISTRY
ISSN:
0955-2863
Año:
2010
Vol.:
21
N°:
8
Págs.:
774 - 780
Adipose tissue is highly vascularized implying that angiogenesis takes place in its expansion. The aim of this study was to compare the concentrations of members of the vascular endothelial growth factor (VEGF) family in obesity. Serum concentrations of VEGFs were analyzed in 15 lean (BMI 20.3+/-2.5 kg/m(2)) and 24 obese (BMI 47.6+/-5.9 kg/m(2)) volunteers. Obese patients showed significantly increased circulating VEGF-A (150+/-104 vs. 296+/-160 pg/ml; P<.05), VEGF-B (2788+/-1038 vs. 4609+/-2202 arbitrary units; P<.05) and VEGF-C (13 453+/-5750 vs. 17 635+/-5117 pg/ml; P<.05) concentrations. Interestingly, levels of VEGF-D were reduced in obese individuals (538+/-301 vs. 270+/-122 pg/ml; P<.01). In addition, VEGF-A significantly decreased after weight loss following Roux-en-Y gastric bypass (BMI from 46.0+/-8.0 to 28.9+/-4.2 kg/m(2)P<.0001 vs. initial) from 345+/-229 to 290+/-216 pg/ml (P<.01). Moreover, in order to corroborate the human findings VEGF-A levels were analyzed during the expansion of adipose tissue in two dynamic models of murine obesity. Serum VEGF-A was significantly increased after 12 weeks on a high-fat diet (43.3+/-9.0 vs. 29.7+/-9.1 pg/ml; P<.01) or in ob/ob mice (52.2+/-18.0 vs. 29.2+/-7.7 pg/ml; P<.01) and was normalized after leptin replacement in the latter (32.4+/-14.0 pg/ml; P<.01 vs. untreated ob/ob). Our data indicates the involvement of these factors in the expansion of adipose tissue that takes place in obesity in relation to the need for increased vascularization, suggesting that manipulation of the VEGF system may represent a potential target for the pharmacological treatment of obesity.
Revista:
OBESITY FACTS
ISSN:
1662-4025
Año:
2010
Vol.:
3
N°:
4
Págs.:
219 - 221
Revista:
MEDIATORS OF INFLAMMATION
ISSN:
0962-9351
Año:
2010
Vol.:
2010
Págs.:
784343
Obese leptin-deficient ob/ob mice exhibit a low-grade chronic inflammation together with a low muscle mass. Our aim was to analyze the changes in muscle expression levels of genes related to oxidative stress and inflammatory responses in leptin deficiency and to identify the effect of in vivo leptin administration. Ob/ob mice were divided in three groups as follows: control ob/ob, leptin-treated ob/ob (1 mg/kg/d) and leptin pair-fed ob/ob mice. Gastrocnemius weight was lower in control ob/ob than in wild type mice (P < .01) exhibiting an increase after leptin treatment compared to control and pair-fed (P < .01) ob/ob animals. Thiobarbituric acid reactive substances, markers of oxidative stress, were higher in serum (P < .01) and gastrocnemius (P = .05) of control ob/ob than in wild type mice and were significantly decreased (P < .01) by leptin treatment. Leptin deficiency altered the expression of 1,546 genes, while leptin treatment modified the regulation of 1,127 genes with 86 of them being involved in oxidative stress, immune defense and inflammatory response. Leptin administration decreased the high expression of Crybb1, Hspb3, Hspb7, Mt4, Cat, Rbm9, Serpinc1 and Serpinb1a observed in control ob/ob mice, indicating that it improves inflammation and muscle loss
Revista:
MEDIATORS OF INFLAMMATION
ISSN:
0962-9351
Año:
2010
Vol.:
2010
Págs.:
105489
Leptin blocks the proliferative response to Ang II through NO-dependent mechanisms. The attenuation of this inhibitory effect of leptin in spontaneous hypertension appears to be due to a reduced NO bioavailability in VSMCs
Revista:
HOT THYROIDOLOGY
ISSN:
2075-2202
Año:
2010
Vol.:
6
N°:
10
Págs.:
1 - 22
Revista:
NUTRITION AND METABOLISM
ISSN:
1743-7075
Año:
2010
Vol.:
7
Págs.:
14
Autores:
Fernández-Real, JM; Catalán, V; Moreno-Navarrete, JM; et al.
Revista:
NUTRITION AND METABOLISM
ISSN:
1743-7075
Año:
2010
Vol.:
7
Págs.:
20
Autores:
Fernández-Real, JM; Valdés, S; Manco, M; et al.
Revista:
DIABETES CARE
ISSN:
0149-5992
Año:
2010
Vol.:
33
N°:
4
Págs.:
847 - 853
Objective: Impaired lung function and innate immunity have both attracted growing interest as a potentially novel risk factor for glucose intolerance, insulin resistance, and type 2 diabetes. We aimed to evaluate whether surfactant protein D (SP-D), a lung-derived innate immune protein, was behind these associations.
Research Design and Methods: Serum SP-D was evaluated in four different cohorts. The cross-sectional associations between SP-D and metabolic and inflammatory parameters were evaluated in two cohorts, the cross-sectional relationship with lung function in one cohort, and the longitudinal effects of weight loss on fasting and circadian rhythm of serum SP-D and cortisol concentrations in one prospective cohort.
Results: In the cross-sectional studies, serum SP-D concentration was significantly decreased in subjects with obesity and type 2 diabetes (P = 0.005) and was negatively associated with fasting and postload serum glucose. SP-D was also associated with A1C, serum lipids, insulin sensitivity, inflammatory parameters, and plasma insulinase activity. Smoking subjects with normal glucose tolerance, but not smoking patients with type 2 diabetes, showed significantly higher serum SP-D concentration than nonsmokers. Serum SP-D concentration correlated positively with end-tidal carbon dioxide tension (r = 0.54, P = 0.034). In the longitudinal study, fasting serum SP-D concentration decreased significantly after weight loss (P = 0.02). Moreover, the main components of cortisol and SP-D rhythms became synchronous after weight loss.
Conclusions: These findings suggest that lung innate immunity, as inferred from circulating SP-D concentrations, is at the cross-roads of inflammation, obesity, and insulin resistance.
Autores:
Ortega, FJ; Vázquez-Martín, A; Moreno-Navarrete, JM; et al.
Revista:
INTERNATIONAL JOURNAL OF OBESITY
ISSN:
0307-0565
Año:
2010
Vol.:
34
N°:
3
Págs.:
487 - 499
