Nuestros investigadores

Fermín Ignacio Milagro Yoldi

Departamento
Ciencias de la Alimentación y Fisiología
Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Efectos anti-inflamatorios, antidiabéticos y antiobesidad de compuestos bioactivos, Búsqueda de nuevos biomarcadores relacionados con la obesidad y la diabetes de tipo 2, tipo genético, transcriptómico y epigenético, Estudio de la regulación de los genes relacionados con la obesidad: miRNAs, epigenética y factores de transcripción, Microbiota en relación con la obesidad y la nutrición, Sexenios CNEAI: 3 (1996-2002; 2003-2008; 2009-2014)
Índice H
37, (Scopus, 08/12/2018)
42, (Google Scholar, 08/12/2018)
35, (WoS, 08/12/2018)

Publicaciones científicas más recientes (desde 2010)

Autores: Gonzalez-Becerra, K.; Ramos-Lopez, O.; Barron-Cabrera, E. ; et al.
Revista: LIPIDS IN HEALTH AND DISEASE
ISSN 1476-511X  Vol. 18  Nº 1  2019 
Background Chronic illnesses like obesity, type 2 diabetes (T2D) and cardiovascular diseases, are worldwide major causes of morbidity and mortality. These pathological conditions involve interactions between environmental, genetic, and epigenetic factors. Recent advances in nutriepigenomics are contributing to clarify the role of some nutritional factors, including dietary fatty acids in gene expression regulation. This systematic review assesses currently available information concerning the role of the different fatty acids on epigenetic mechanisms that affect the development of chronic diseases or induce protective effects on metabolic alterations. Methods A targeted search was conducted in the PubMed/Medline databases using the keywords "fatty acids and epigenetic". The data were analyzed according to the PRISMA-P guidelines. Results Consumption fatty acids like n-3 PUFA: EPA and DHA, and MUFA: oleic and palmitoleic acid was associated with an improvement of metabolic alterations. On the other hand, fatty acids that have been associated with the presence or development of obesity, T2D, pro-inflammatory profile, atherosclerosis and IR were n-6 PUFA, saturated fatty acids (stearic and palmitic), and trans fatty acids (elaidic), have been also linked with epigenetic changes. Conclusions Fatty acids can regulate gene expression by modifying epigenetic mechanisms and consequently result in positive or negative impacts on metabolic outcomes.
Autores: Lorente, Silvia, (Autor de correspondencia); González-Muniesa, P; Milagro FI; et al.
Revista: CLINICAL SCIENCE
ISSN 0143-5221  Vol. 133  Nº 1  2019  págs. 23 - 40
Obesity is a metabolic condition usually accompanied by insulin resistance (IR), type 2 diabetes (T2D), and dyslipidaemia, which is characterised by excessive fat accumulation and related to white adipose tissue (WAT) dysfunction. Enlargement of WAT is associated with a transcriptional alteration of coding and non-coding RNAs (ncRNAs). For many years, big efforts have focused on understanding protein-coding RNAs and their involvement in the regulation of adipocyte physiology and subsequent role in obesity. However, diverse findings have suggested that a dysfunctional adipocyte phenotype in obesity might be also dependent on specific alterations in the expression pattern of ncRNAs, such as miRNAs. The aim of this review is to update current knowledge on the physiological roles of miRNAs and other ncRNAs in adipose tissue function and their potential impact on obesity. Therefore, we examined their regulatory role on specific WAT features: adipogenesis, adipokine secretion, inflammation, glucose metabolism, lipolysis, lipogenesis, hypoxia and WAT browning. MiRNAs can be released to body fluids and can be transported (free or inside microvesicles) to other organs, where they might trigger metabolic effects in distant tissues, thus opening new possibilities to a potential use of miRNAs as biomarkers for diagnosis, prognosis, and personalisation of obesity treatment. Understanding the role of miRNAs also opens the possibility of using these molecules on individualised dietary strategies for precision weight management. MiRNAs should be envisaged as a future therapeutic approach given that miRNA levels could be modulated by synthetic molecules (f.i. miRNA mimics and inhibitors) and/or specific nutrients or bioactive compounds.
Autores: Barron-Cabrera, E. ; Ramos-Lopez, O.; Gonzalez-Becerra, K.; et al.
Revista: LIFESTYLE GENOMICS
ISSN 2504-3161  Vol. 12  Nº 1  2019  págs. 25 - 44
Background: Chronic diseases arise as a consequence of an unhealthy lifestyle primarily characterized by physical inactivity and unbalanced diets. Regular physical activity can improve health, and there is consistent evidence that these improvements may be the result of epigenetic modifications. Objective: To identify epigenetic modificationsas outcomes of exercise interventions related to specific metabolic alterations. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) methodology for manuscript research and preparation was followed using PubMed and EBSCO databases for literature review. Out of 2,638 articles identified, only 34 articles met the inclusion criteria. Results: The sections of the review were organized by metabolic alterations in which studies were grouped according to healthy, diseased, and trained individuals. Resistance exercise in humans induced epigenetic changes in pathways associated with energy metabolism and insulin sensitivity, contributing to healthy skeletal muscle. Endurance exercise also caused modifications in biomarkers associated to metabolic alterations through changes in DNA methylation and the expression of specific miRNAs. However, both resistance and endurance exercise are necessary to obtain a better physiological adaptation and a combination of both seems to be needed to properly tackle the increasing prevalence of non-communicable pathologies. Conclusion: Given the heterogeneity and complexity of the existing literature, it is currently not possible to propose a specific recommendation about the type, intensity, or duration of exercise that could be beneficial for different subsets of the population (healthy, diseased, and/or trained). Nevertheless, this review highlights the importance of exercise for health and shows the need to perform more research in this emerging area to identify epigenetic biomarkers that could serve as indicators of exercise adaptations.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: FRONTIERS IN GENETICS
ISSN 1664-8021  Vol. 10  2019 
Aim: To analyze the influence of genetics and interactions with environmental factors on adiposity outcomes [waist circumference reduction (WCR) and total body fat loss (TFATL)] in response to energy-restricted diets in subjects with excessive body weight. Materials and Methods: Two hypocaloric diets (30% energy restriction) were prescribed to overweight/obese subjects during 16 weeks, which had different targeted macronutrient distribution: a low-fat (LF) diet (22% energy from lipids) and a moderately high-protein (MHP) diet (30% energy from proteins). At the end of the trial, a total of 201 participants (LF diet = 105; MHP diet = 96) who presented good/regular dietary adherence were genotyped for 95 single nucleotide polymorphisms (SNPs) previously associated with weight loss through next-generation sequencing from oral samples. Four unweighted (uGRS) and four weighted (wGRS) genetic risk scores were computed using statistically relevant SNPs for each outcome by diet. Predictions of WCR and TFATL by diet were modeled through recognized multiple linear regression models including genetic (single SNPs, uGRS, and wGRS), phenotypic (age, sex, and WC, or TFAT at baseline), and environment variables (physical activity level and energy intake at baselines) as well as eventual interactions between genes and environmental factors. Results: Overall, 26 different SNPs were associated with differential adiposity outcomes, 9 with WCR and 17 with TFATL, most of which were specific for each dietary intervention. In addition to conventional predictors (age, sex, lifestyle, and adiposity status at baseline), the calculated uGRS/wGRS and interactions with environmental factors were major contributors of adiposity responses. Thus, variances in TFATL-LF diet, TFATL-MHP diet, WCR-LF diet, and WCR-MHP diet were predicted by approximately 38% (optimism-corrected adj. R-2 = 0.3792), 32% (optimism-corrected adj. R-2 = 0.3208), 22% (optimism-corrected adj. R-2 = 0.2208), and 21% (optimism-corrected adj. R-2 = 0.2081), respectively. Conclusions: Different genetic variants and interactions with environmental factors modulate the differential individual responses to MHP and LF dietary interventions. These insights and models may help to optimize personalized nutritional strategies for modeling the prevention and management of excessive adiposity through precision nutrition approaches taking into account not only genetic information but also the lifestyle/clinical factors that interplay in addition to age and sex.
Autores: Arpon, Ana; Milagro FI; Ramos-Lopez, O.; et al.
Revista: SCIENTIFIC REPORTS
ISSN 2045-2322  Vol. 9  Nº 1  2019 
Insulin resistance (IR) is a hallmark of type 2 diabetes, metabolic syndrome and cardiometabolic risk. An epigenetic phenomena such as DNA methylation might be involved in the onset and development of systemic IR. The aim of this study was to explore the genetic DNA methylation levels in peripheral white blood cells with the objective of identifying epigenetic signatures associated with IR measured by the Homeostatic Model Assessment of IR (HOMA-IR) following an epigenome-wide association study approach. DNA methylation levels were assessed using Infinium Methylation Assay (Illumina), and were associated with HOMA-IR values of participants from the Methyl Epigenome Network Association (MENA) project, finding statistical associations for at least 798 CpGs. A stringent statistical analysis revealed that 478 of them showed a differential methylation pattern between individuals with HOMA-IR <= 3 and > 3. ROC curves of top four CpGs out of 478 allowed differentiating individuals between both groups (AUC approximate to 0.88). This study demonstrated the association between DNA methylation in some specific CpGs and HOMA-IR values that will help to the understanding and in the development of new strategies for personalized approaches to predict and prevent IR-associated diseases.
Autores: Marín-Alejandre, B. A.; Abete, Itziar; Cantero, Irene; et al.
Revista: NUTRIENTS
ISSN 2072-6643  Vol. 11  Nº 2  2019  págs. 322
The relevance of sleep patterns in the onset or evolution of nonalcoholic fatty liver disease (NAFLD) is still poorly understood. Our aim was to investigate the association between sleep characteristics and hepatic status indicators in obese people with NAFLD compared to normal weight non-NAFLD controls. Ninety-four overweight or obese patients with NAFLD and 40 non-NAFLD normal weight controls assessed by abdominal ultrasonography were enrolled. Hepatic status evaluation considered liver stiffness determined by Acoustic Radiation Force Impulse elastography (ARFI) and transaminases. Additionally, anthropometric measurements, clinical characteristics, and biochemical profiles were determined. Sleep features were evaluated using the Pittsburgh Sleep Quality Index (PSQI). Hepatic status parameters, anthropometric measurements, and clinical and biochemical markers differed significantly in NAFLD subjects compared to controls, as well as sleep efficiency, sleep disturbance score, and sleep quality score. In the NAFLD group, a higher prevalence of short sleep duration (p = 0.005) and poor sleep quality (p = 0.041) were found. Multivariate-adjusted odds ratio (95% confidence interval) for NAFLD considering sleep disturbance was 1.59 (1.11¿2.28). Regression models that included either sleep disturbance or sleep quality predicted up to 20.3% and 20.4% of the variability of liver stiffness, respectively, and after adjusting for potential confounders. Current findings suggest that sleep disruption may be contributing to the pathogenesis of NAFLD as well as the alteration of the liver may be affecting sleep patterns. Consequently, sleep characteristics may be added to the list of modifiable behaviors to consider in health promotion strategies and in the prevention and management of NAFLD.
Autores: Salas-Perez, F. ; Ramos-Lopez, O.; Mansego, Maria L; et al.
Revista: AGING-US
ISSN 1945-4589  Vol. 11  Nº 6  2019  págs. 1874 - 1899
Aging is the main risk factor for most chronic diseases. Epigenetic mechanisms, such as DNA methylation (DNAm) plays a pivotal role in the regulation of physiological responses that can vary along lifespan. The aim of this research was to analyze the association between leukocyte DNAm in genes involved in longevity and the occurrence of obesity and related metabolic alterations in an adult population. Subjects from the MENA cohort (n=474) were categorized according to age (<45 vs 45>) and the presence of metabolic alterations: increased waist circumference, hypercholesterolemia, insulin resistance, and metabolic syndrome. The methylation levels of 58 CpG sites located at genes involved in longevity-regulating pathways were strongly correlated (FDRadjusted< 0.0001) with BMI. Fifteen of them were differentially methylated (p<0.05) between younger and older subjects that exhibited at least one metabolic alteration. Six of these CpG sites, located at MTOR (cg08862778), ULK1 (cg07199894), ADCY6 (cg11658986), IGF1R (cg01284192), CREB5 (cg11301281), and RELA (cg08128650), were common to the metabolic traits, and CREB5, RELA, and ULK1 were statistically associated with age. In summary, leukocyte DNAm levels of several CpG sites located at genes involved in longevity-regulating pathways were associated with obesity and metabolic syndrome traits, suggesting a role of DNAm in aging-related metabolic alterations.
Autores: Assmann, T. S.; Milagro FI; Martínez, JA, (Autor de correspondencia)
Revista: MOLECULAR MEDICINE REPORTS
ISSN 1791-2997  Vol. 20  Nº 4  2019  págs. 3543 - 3554
MicroRNAs (miRNAs/miRs) are small non-coding RNAs (ncRNAs) that regulate gene expression. Emerging knowledge has suggested that miRNAs have a role in the pathogenesis of metabolic disorders, supporting the hypothesis that miRNAs may represent potential biomarkers or targets for this set of diseases. However, the current evidence is often controversial. Therefore, the aim of the present study was to determine the associations between miRNAs-target genes, miRNA-long ncRNAs (lncRNAs), and miRNAs-small molecules in human metabolic diseases, including obesity, type 2 diabetes and non-alcoholic fatty liver disease. The metabolic disease-related miRNAs were obtained from the Human MicroRNA Disease Database (HMDD) and miR2Disease database. A search on the databases Matrix Decomposition and Heterogeneous Graph Inference (MDHGI) and DisGeNET were also performed. miRNAs target genes were obtained from three independent sources: Microcosm, TargetScan and miRTarBase. The interactions between miRNAs-lncRNA and miRNA-small molecules were performed using the miRNet web tool. The network analyses were performed using Cytoscape software. As a result, a total of 20 miRNAs were revealed to be associated with metabolic disorders in the present study. Notably, 6 miRNAs (miR-17-5p, miR-29c-3p, miR-34a-5p, miR-103a-3p, miR-107 and miR-132-3p) were found in the four resources (HMDD, miR2Disease, MDHGI, and DisGeNET) used for these analyses, presenting a stronger association with the diseases. Furthermore, the target genes of these miRNAs participate in several pathways previously associated with metabolic diseases. In addition, interactions between miRNA-lncRNA and miRNA-small molecules were also found, suggesting that some molecules can modulate gene expression via such an indirect way. Thus, the results of this data mining and integration analysis provide further information on the possible molecular basis of the metabolic disease pathogenesis as well as provide a path to search for potential biomarkers and therapeutic targets concerning metabolic diseases.
Autores: Cuevas-Sierra, A.; Ramos-López, O.; Riezu-Boj, José Ignacio; et al.
Revista: ADVANCES IN NUTRITION
ISSN 2161-8313  Vol. 10  Nº Suppl.1   2019  págs. S17 - S30
Diverse evidence suggests that the gut microbiota is involved in the development of obesity and associated comorbidities. It has been reported that the composition of the gut microbiota differs in obese and lean subjects, suggesting that microbiota dysbiosis can contribute to changes in body weight. However, the mechanisms by which the gut microbiota participates in energy homeostasis are unclear. Gut microbiota can be modulated positively or negatively by different lifestyle and dietary factors. Interestingly, complex interactions between genetic background, gut microbiota, and diet have also been reported concerning the risk of developing obesity and metabolic syndrome features. Moreover, microbial metabolites can induce epigenetic modifications (i.e., changes in DNA methylation and micro-RNA expression), with potential implications for health status and susceptibility to obesity. Also, microbial products, such as short-chain fatty acids or membrane proteins, may affect host metabolism by regulating appetite, lipogenesis, gluconeogenesis, inflammation, and other functions. Metabolomic approaches are being used to identify new postbiotics with biological activity in the host, allowing discovery of new targets and tools for incorporation into personalized therapies. This review summarizes the current understanding of the relations between the human gut microbiota and the onset and development of obesity. These scientific insights are paving the way to understanding the complex relation between obesity and microbiota. Among novel approaches, prebiotics, probiotics, postbiotics, and fecal microbiome transplantation could be useful to restore gut dysbiosis.
Autores: Aranaz, Paula; Navarro-Herrera, D.; Romo, Ana; et al.
Revista: JOURNAL OF FUNCTIONAL FOODS
ISSN 1756-4646  Vol. 59  2019  págs. 319 - 328
Brassicaceae contain bioactive compounds with potential positive effects on metabolic syndrome. Here, we evaluated the eventual anti-obesity properties of an ethanolic broccoli extract (BE), selected by a tested ability to reduce Caenorhabditis elegans fat content. Two doses (14 and 140 mg/kg animal) of BE were evaluated in a diet-induced obesity (DIO) Wistar rat model. After 10 weeks of BE supplementation, animals exhibited reduced body weight gain and food efficiency, decreased atherogenic index of plasma and improved glucose tolerance in comparison with non-supplemented rats. BE also reduced the retroperitoneal fat mass and adipocyte size, all associated to down-regulation of Cebpa, Srebp1, Fasn and Adipoq expression in adipocytes. Finally, BE significantly decreased liver steatosis, accompanied by the up-regulation of Acot8 and Acox1, and the down-regulation of Fasn, Fatp4 and Srebf1 expression in hepatocytes. Our data provides new knowledge about the potential role of broccoli components in the prevention of metabolic syndrome.
Autores: Arpon, Ana; Santos, J. L., (Autor de correspondencia); Milagro FI; et al.
Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067  Vol. 20  Nº 12  2019 
Hyperglycaemia and type 2 diabetes (T2D) are associated with impaired insulin secretion and/or insulin action. Since few studies have addressed the relation between DNA methylation patterns with elaborated surrogates of insulin secretion/sensitivity based on the intravenous glucose tolerance test (IVGTT), the aim of this study was to evaluate the association between DNA methylation and an insulin sensitivity index based on IVGTT (calculated insulin sensitivity index (CSi)) in peripheral white blood cells from 57 non-diabetic female volunteers. The CSi and acute insulin response (AIR) indexes, as well as the disposition index (DI = CSi x AIR), were estimated from abbreviated IVGTT in 49 apparently healthy Chilean women. Methylation levels were assessed using the Illumina Infinium Human Methylation 450k BeadChip. After a statistical probe filtering, the two top CpGs whose methylation was associated with CSi were cg04615668 and cg07263235, located in the catenin delta 2 (CTNND2) and lipoprotein lipase (LPL) genes, respectively. Both CpGs conjointly predicted insulin sensitivity status with an area under the curve of 0.90. Additionally, cg04615668 correlated with homeostasis model assessment insulin-sensitivity (HOMA-S) and AIR, whereas cg07263235 was associated with plasma creatinine and DI. These results add further insights into the epigenetic regulation of insulin sensitivity and associated complications, pointing the CTNND2 and LPL genes as potential underlying epigenetic biomarkers for future risk of insulin-related diseases.
Autores: Carraro, J. C.; Martínez, JA; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 75  Nº 3  2019  págs. 341 - 349
Fatty acids (FAs) are known to participate in body inflammatory responses. In particular, saturated FAs such as palmitic acid (PA) induce inflammatory signals in macrophages, whereas polyunsaturated FAs, including docosahexaenoic acid (DHA), have been related to anti-inflammatory effects. Several studies have suggested a role of fatty acids on DNA methylation, epigenetically regulating gene expression in inflammation processes. Therefore, this study investigated the effect of PA and DHA on the inflammation-related genes on human macrophages. In addition, a second aim was to study the epigenetic mechanism underlying the effect of FAs on the inflammatory response. For these purposes, human acute monocytic leukaemia cells (THP-1) were differentiated into macrophages with 12-O-tetradecanoylphorbol-13-acetate (TPA), followed by an incubation with PA or DHA. At the end of the experiment, mRNA expression, protein secretion, and CpG methylation of the following inflammatory genes were analysed: interleukin 1 beta (IL1B), tumour necrosis factor (TNF), plasminogen activator inhibitor-1 (SERPINE1) and interleukin 18 (IL18). The results showed that the treatment with PA increased IL-18 and TNF-alpha production. Contrariwise, the supplementation with DHA reduced IL-18, TNF-alpha and PAI-1 secretion by macrophages. However, the incubation with these fatty acids did not apparently modify the DNA methylation status of the investigated genes in the screened CpG sites. This research reveals that PA induces important pro-inflammatory markers in human macrophages, whereas DHA decreases the inflammatory response. Apparently, DNA methylation is not directly involved in the fatty acid-mediated regulation of the expression of these inflammation-related genes.
Autores: Santos, J. L., (Autor de correspondencia); Cataldo, L. R.; Cortés-Rivera, C.; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 75  Nº 3  2019  págs. 285 - 297
High plasma lactate levels have been associated with reduced mitochondrial respiratory capacity and increased type 2 diabetes risk, while mitochondrial DNA (mtDNA) copy number has been proposed as a biomarker of mitochondrial function linked to glucose homeostasis. The aim of this study was to evaluate the association between circulating lactate levels and leukocyte mtDNA copy numbers with insulin secretion/sensitivity indexes in 65 Chilean non-diabetic women. mtDNA copy numbers were measured in leukocytes using qPCR and digital-droplet PCR. A 75-g Oral Glucose Tolerance Test (OGTT) was performed to calculate systemic and tissue-specific insulin sensitivity indexes, as well as insulin secretion surrogates based on plasma c-peptide. An intravenous glucose tolerance test (IVGTT; 0.3 g/kg) was also carried out. Disposition indexes were calculated as the product of insulin secretion × sensitivity. Plasma levels of leptin, adiponectin, TNF-¿, MCP-1, and non-esterified fatty acids were also determined. Fasting plasma lactate shows a significant association with a wide range of insulin sensitivity/resistance indexes based on fasting plasma samples (HOMA-S, adipose IR index, Revised-QUICKI, leptin-adiponectin ratio, TyG index, McAuley index and TG-to-HDL-C ratio), as well as OGTT-based measures such as the Matsuda index, the hepatic insulin resistance index, and the disposition index. Fasting plasma lactate was also positively associated with the circulating adipokines TNF-¿ and MCP-1. We also detected a direct association between fasting plasma lactate with leukocyte mtDNA copy numbers. The above results support the use of fasting plasma lactate, and possibly leukocyte mtDNA copy numbers, as biomarkers of reduced oxidative mitochondrial capacity, decreased hepatic insulin sensitivity, and future diabetes risk.
Autores: Arpon, Ana; Milagro FI; Santos, J. L.; et al.
Revista: FRONTIERS IN ENDOCRINOLOGY
ISSN 1664-2392  Vol. 10  2019 
The distribution of adipose tissue is influenced by gender and by age, shifting from subcutaneous to visceral depots with longevity, increasing the development of several aging-related diseases and manifestations such as obesity, metabolic syndrome, and insulin resistance. Epigenetics might have an important role in aging processes. The aim of this research was to investigate the interactions between aging and epigenetic processes and the role of visceral adipose tissue, insulin resistance, and dyslipidaemia. Two different study samples of 366 and 269 adult participants were analyzed. Anthropometric, biochemical (including the triglycerides-glucose (TyG) index), and blood pressure measurements were assessed following standardized methods. Body composition measurements by Dual-energy X-ray absorptiometry (DXA) were also performed for the second sample. Methylation data were assessed by Infinium Human Methylation BeadChip (Illumina) in peripheral white blood cells. Epigenetic age acceleration was calculated using the methods DNAmAge (AgeAcc) and GrimAge (AgeAccGrim). Age acceleration (AgeAccGrim) showed better correlations than AgeAcc with most of the measured variables (waist circumference, glucose, HOMA-IR, HDL-cholesterol, triglycerides, and TyG index) for the first sample. In the second sample, all the previous correlations were confirmed, except for HOMA-IR. In addition, many of the anthropometricalmeasurements assessed by DXA and C-reactive protein (CRP) were also statistically associated with AgeAccGrim. Associations separated by sex showed statistically significant correlations between AgeAccGrim and HDL-cholesterol or CRP in women, whereas, in men, the association was with visceral adipose tissue mass DXA, triglycerides and TyG index. Linear regression models (model 1 included visceral adipose tissuemass DXA and TyGindex andmodel 2 included HDL-cholesterol and CRP) showed a significant association for men concerning visceral adipose tissue mass DXA and TyG index, while HDL-cholesterol and CRP were associated in women. Moreover, structural equation modeling showed that the TyG index was mediating the majority of the visceral adipose tissue mass action on age acceleration. Collectively, these findings showed that there are different mechanisms affecting epigenetic age acceleration depending on sex. The identified relationships between epigenetic age acceleration and disease markers will contribute to the understanding of the development of age-related diseases.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: THERAPEUTIC ADVANCES IN ENDOCRINOLOGY AND METABOLISM
ISSN 2042-0188  Vol. 10  2019  págs. 1 - 12
Autores: Mercader, J., (Autor de correspondencia); Sabater, A. G.; Le Gonidec, S. ; et al.
Revista: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN 0022-3565  Vol. 371  Nº 2  2019  págs. 555 - 566
Novel mechanisms and health benefits have been recently suggested for the antidepressant drug phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Senn icarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL
ISSN 0163-5581  Vol. 71  Nº 5  2019  págs. 840 - 851
Obesity and type 2 diabetes mellitus are independent risk factors for the onset and progression of hepatocellular carcinoma (HCC). This study aimed to analyze the association of DNA methylation signatures at HCC pathway genes with obesity and related metabolic disturbances. A population of 474 adults within the Methyl Epigenome Network Association (MENA) project was included. DNA methylation levels were measured in white blood cells by microarray. The identification and discrimination of HCC pathway genes were performed using KEGG and PathDIP databases. Anthropometry measurements, the blood metabolic profile, and clinical data were analyzed. The methylation patterns of 20 CpG sites at HCC pathway genes strongly correlated with BMI (FDR <0.0001). These genes encompassed GADD45A, MTOR, FRAT2, E2F3, WNT7B, FRAT1, LRP5, DPF3, GSTA2, APC, MYC, WNT10B, ARID1B, AKT1, GSTA1, WNT5A, CDK4, GAB1, TCF7, which statistically contributed to the regulation of the HCC pathway (P = 2.10e-07). The main biological process where these genes were implicated included uncontrolled cell proliferation, DNA damage, increased survival, and altered oncogenic expression. Interestingly, 9 out of 20 BMI-associated CpGs also correlated with waist circumference and HOMA-IR index. In conclusion, pathway analysis revealed potential associations of DNA methylation signatures at HCC pathway genes with adiposity and insulin resistance phenotypes.
Autores: Rodriguez-Lozada, C.; Cuervo, M, (Autor de correspondencia); et al.
Revista: NUTRIENTS
ISSN 2072-6643  Vol. 11  Nº 6  2019  págs. E1206
Current evidence proposes diet quality as a modifiable risk factor for mental or emotional impairments. However, additional studies are required to investigate the effect of dietary patterns and weight loss on improving psychological symptoms. The aim of this investigation was to evaluate the effect of energy-restriction, prescribed to overweight and obese participants, on anxiety and depression symptoms, as well as the potential predictive value of some baseline psychological features on weight loss. Overweight and obese participants (n = 305) were randomly assigned for 16 weeks to two hypocaloric diets with different macronutrient distribution: a moderately high-protein (MHP) diet and a low-fat (LF) diet. Anthropometrical, clinical, psychological, and lifestyle characteristics were assessed at baseline and at the end of the intervention. The nutritional intervention evidenced that weight loss has a beneficial effect on trait anxiety score in women (beta = 0.24, p = 0.03), depression score in all population (beta = 0.15, p = 0.02), particularly in women (beta = 0.22, p = 0.03) and in subjects who followed the LF diet (beta = 0.22, p = 0.04). Moreover, weight loss could be predicted by anxiety status at baseline, mainly in women and in those who were prescribed a LF diet. This trial suggests that weight loss triggers an improvement in psychological traits, and that anxiety symptoms could predict those volunteers that benefit most from a balanced calorie-restricted intervention, which will contribute to individualized precision nutrition.
Autores: Mansego, Maria L; Zulet, María de los Ángeles; et al.
Revista: EUROPEAN JOURNAL OF NUTRITION
ISSN 1436-6207  Vol. 58  Nº 5  2019  págs. 1971 - 1980
Purpose The interindividual variable response to weight-loss treatments requires the search for new predictive biomarkers for improving the success of weight-loss programs. The aim of this study is to identify novel genes that distinguish individual responses to a weight-loss dietary treatment by using the integrative analysis of mRNA expression and DNA methylation arrays. Methods Subjects from Metabolic Syndrome Reduction in Navarra (RESMENA) project were classified as low (LR) or high (HR) responders depending on their weight loss. Transcriptomic (n=24) and epigenomic (n=47) patterns were determined by array-based genome-wide technologies in human white blood cells at the baseline of the treatment period. CD44 expression was validated by qRT-PCR and methylation degree of CpGs of the gene was validated by MassARRAY((R)) EpiTYPER (TM) in a subsample of 47 subjects. CD44 protein levels were measured by ELISA in human plasma. Results Different expression and DNA methylation profiles were identified in LR in comparison to HR. The integrative analysis of both array data identified four genes: CD44, ITPR1, MTSS1 and FBXW5 that were differently methylated and expressed between groups. CD44 showed higher expression and lower DNA methylation levels in LR than in HR. Although differences in CD44 protein levels between LR and HR were not statistically significant, a positive association was observed between CD44 mRNA expression and protein levels. Conclusions In summary, the combination of a genome-wide methylation and expression array dataset can be a useful strategy to identify novel genes that might be considered as predictors of the dietary response. CD44 gene transcription and methylation may be a possible candidate biomarker for weight-loss prediction.
Autores: Aranaz, Paula; Navarro Herrera, D.; et al.
Revista: MOLECULES
ISSN 1420-3049  Vol. 24  Nº 6  2019  págs. 1 - 21
Phenolic compounds might modulate adiposity. Here, we report our observation that polyphenols and phenolic acids inhibit adipogenesis in 3T3-L1 with different intensity depending on the family and the stage of differentiation. While quercetin and resveratrol inhibited lipid accumulation along the whole process of differentiation, apigenin and myricetin were active during the early and latest stages, but not intermediate, contrary to hesperidin. The activity of phenolic acids was limited to the early stages of the differentiation process, except p-coumaric and ellagic acids. This anti-adipogenic effect was accompanied by down-regulation of Scd1 and Lpl. Molecular docking analysis revealed that the inhibitory activity of these phenolic compounds over the early stages of adipogenesis exhibits a significant correlation (r = 0.7034; p = 0.005) with their binding affinity to the ligand-binding domain of PPAR¿. Results show that polyphenols and phenolic acids would interact with specific residues of the receptor, which could determine their potential anti-adipogenic activity during the early stages of the differentiation. Residues Phe264, His266, Ile281, Cys285 and Met348 are the most frequently involved in these interactions, which might suggest a crucial role for these amino acids modulating the activity of the receptor. These data contribute to elucidate the possible mechanisms of phenolic compounds in the control of adipogenesis.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: GENES AND NUTRITION
ISSN 1555-8932  Vol. 14  2019  págs. 11
BACKGROUND: Olfaction is an important sense influencing food preferences, appetite, and eating behaviors. This hypothesis-driven study aimed to assess associations between olfactory pathway gene methylation signatures, obesity features, and dietary intakes. METHODS: A nutriepigenomic analysis was conducted in 474 adults from the Methyl Epigenome Network Association (MENA) project. Anthropometric measurements, clinical data, and serum metabolic profiles of the study population were obtained from structured databases of the MENA cohorts. Habitual dietary intake was assessed using a validated semiquantitative food frequency questionnaire. DNA methylation was measured in circulating white blood cells by microarray (Infinium Human Methylation 450¿K BeadChips). FDR values (p <¿0.0001) were used to select those CpGs that showed the best correlation with body mass index (BMI) and waist circumference (WC). Pathway analyses involving the characterization of genes involved in the olfactory transduction system were performed using KEGG and pathDIP reference databases. RESULTS: Overall, 15 CpG sites at olfactory pathway genes were associated with BMI (p <¿0.0001) and WC (p <¿0.0001) after adjustments for potential confounding factors. Together, methylation levels at the15 CpG sites accounted for 22% and 20% of the variability in BMI and WC (r 2 =¿0.219, p <¿0.001, and r 2 =¿0.204, p <¿0.001, respectively). These genes encompassed olfactory receptors (OR4D2, OR51A7, OR2T34, and OR2Y1) and several downstream signaling molecules (SLC8A1, ANO2, PDE2A, CALML3, GNG7, CALML6, PRKG1, and CAMK2D), which significantly regulated odor detection and signal transduction processes within the complete olfactory cascade, as revealed by pathway enrichment analyses (p =¿1.94¿×¿10-10). Moreover, OR4D2 and OR2Y1 gene methylation patterns strongly correlated with daily intakes of total energy (p <¿0.0001), carbohydrates (p <¿0.0001), protein (p <¿0.0001), and fat (p <¿0.0001). CONCLUSIONS: The results of this study suggest novel relationships between olfactory pathway gene methylation signatures, obesity indices, and dietary intakes.
Autores: Aranaz, Paula; Romo, Ana; Navarro-Herrera, D.; et al.
Revista: FOOD & FUNCTION
ISSN 2042-6496  Vol. 10  Nº 8  2019  págs. 4811 - 4822
Cocoa polyphenols exhibit high antioxidant activity and have been proposed as a potential adjuvant for the treatment of metabolic disturbances. Here, we demonstrate that supplementation with low doses (14 and 140 mg per kg per rat) of a complete cocoa extract induces metabolic benefits in a diet-induced obesity (DIO) model of Wistar rats. After 10 weeks, cocoa extract-supplemented animals exhibited significantly lower body weight gain and food efficiency, with no differences in energy intake. Cocoa significantly reduced visceral (epididymal and retroperitoneal) and subcutaneous fat accumulation accompanied by a significant reduction in the adipocyte size, which was mediated by downregulation of the adipocyte-specific genes Cebpa, Fasn and Adipoq. Additionally, cocoa extract supplementation reduced the triacylglycerol/high density lipoprotein (TAG/HDL) ratio, decreased hepatic triglyceride accumulation, improved insulin sensitivity by reducing HOMA-IR, and significantly ameliorated glucose tolerance after an intraperitoneal glucose tolerance test. Finally, no adverse effect was observed in an in vivo toxicity evaluation of our cocoa extract at doses up to 500 mg kg -1 day -1. Our data demonstrate that low doses of cocoa extract supplementation (14 and 140 mg kg -1 day -1) are safe and sufficient to counteract obesity and type-2 diabetes in rats and provide new insights into the potential application of cocoa supplements in the management of the metabolic syndrome.
Autores: Arpon, Ana; Milagro FI; Ramos-Lopez, O.; et al.
Revista: GENES
ISSN 2073-4425  Vol. 10  Nº 6  2019 
Epigenetic signatures such as DNA methylation may be associated with specific obesity traits in different tissues. The onset and development of some obesity-related complications are often linked to visceral fat accumulation. The aim of this study was to explore DNA methylation levels in peripheral white blood cells to identify epigenetic methylation marks associated with waist circumference (WC). DNA methylation levels were assessed using Infinium Human Methylation 450K and MethylationEPIC beadchip (Illumina) to search for putative associations with WC values of 473 participants from the Methyl Epigenome Network Association (MENA) project. Statistical analysis and Ingenuity Pathway Analysis (IPA) were employed for assessing the relationship between methylation and WC. A total of 669 CpGs were statistically associated with WC (FDR < 0.05, slope >= |0.1|). From these CpGs, 375 CpGs evidenced a differential methylation pattern between females with WC <= 88 and > 88 cm, and 95 CpGs between males with WC <= 102 and > 102 cm. These differentially methylated CpGs are located in genes related to inflammation and obesity according to IPA. Receiver operating characteristic (ROC) curves of the top four significant differentially methylated CpGs separated by sex discriminated individuals with presence or absence of abdominal fat. ROC curves of all the CpGs from females and one CpG from males were validated in an independent sample (n = 161). These methylation results add further insights about the relationships between obesity, adiposity-associated comorbidities, and DNA methylation where inflammation processes may be involved.
Autores: Aranaz, Paula; Navarro-Herrera, D.; Romo, Ana; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 75  2019  págs. 49 - 49
Autores: Assmann, T. S.; Milagro FI; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 75  2019  págs. 43 - 44
Autores: Salas-Perez, F.; Assmann, TS; Riezu-Boj, José Ignacio; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 75  Nº Supl. 2  2019  págs. 53 - 54
Autores: Riezu-Boj, José Ignacio; Guruceaga, Elisabet; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 75  Nº Supl. 2  2019  págs. 18 - 18
Autores: Ramírez, M.J.; Milagro FI; et al.
Revista: NUTRIENTS
ISSN 2072-6643  Vol. 10  Nº 10  2018 
Trimethylamine N-oxide (TMAO) is a molecule generated from choline, betaine, and carnitine via gut microbial metabolism. The plasma level of TMAO is determined by several factors including diet, gut microbial flora, drug administration and liver flavin monooxygenase activity. In humans, recent clinical studies evidence a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events. A direct correlation between increased TMAO levels and neurological disorders has been also hypothesized. Several therapeutic strategies are being explored to reduce TMAO levels, including use of oral broad spectrum antibiotics, promoting the growth of bacteria that use TMAO as substrate and the development of target-specific molecules. Despite the accumulating evidence, it is questioned whether TMAO is the mediator of a bystander in the disease process. Thus, it is important to undertake studies to establish the role of TMAO in human health and disease. In this article, we reviewed dietary sources and metabolic pathways of TMAO, as well as screened the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and neurological disorders, underlying the importance of TMAO mediating inflammatory processes. Finally, the potential utility of TMAO as therapeutic target is also analyzed.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: ADIPOCYTE
ISSN 2162-3945  Vol. 7  Nº 2  2018  págs. 137 - 142
Unresolved ER stress is involved in the onset and progression of several obesity-related metabolic disorders, including dyslipidemia and insulin resistance. Different epigenetic modifications may regulate ER stress response and consequently disease risks. These epigenetic phenomena encompass DNA and histone methylation patterns in ER stress genes and downstream signaling molecules, as well as microRNA expression. Our results suggest potential associations of methylation signatures at ER regulatory genes in white blood cells with an abdominal/central obesity marker (waist circumference), dyslipidemia, and insulin resistance. Interestingly, most of these genes were implicated in ER stress, as revealed by pathway enrichment analysis. Together, these findings add knowledge into the current understanding of relationships between obesity and accompanying complications with epigenetics and ER stress. Here, we comment about the implication of ER stress in central/abdominal adiposity, dyslipidemia, and insulin resistance, with an emphasis on the role that epigenetics may play on these pathological processes.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: BRAIN AND BEHAVIOR
ISSN 2162-3279  Vol. 8  Nº 8  2018 
Introduction: Dopamine (DA) is a neurotransmitter that regulates the rewarding and motivational processes underlying food intake and eating behaviors. This study hypothesized associations of DNA methylation signatures at genes modulating DA signaling with obesity features, metabolic profiles, and dietary intake. Methods: An adult population within the Methyl Epigenome Network Association project was included (n = 473). DNA methylation levels in white blood cells were measured by microarray (450K). Differentially methylated genes were mapped within the dopaminergic synapse pathway using the KEGG reference database (map04728). Subsequently, network enrichment analyses were run in the pathDIP portal. Associations of methylation patterns with anthropometric markers of general (BMI) and abdominal obesity (waist circumference), the blood metabolic profile, and daily dietary intakes were screened. Results: After applying a correction for multiple comparisons, 12 CpG sites were strongly associated (p < 0.0001) with BMI: cg03489495 (ITPR3), cg22851378 (PPP2R2D), cg04021127 (PPP2R2D), cg22441882 (SLC18A1), cg03045635 (DRD5), cg23341970 (ITPR2), cg13051970 (DDC), cg08943004 (SLC6A3), cg20557710 (CACNA1C), cg24085522 (GNAL), cg16846691 (ITPR2), and cg09691393 (SLC6A3). Moreover, average methylation levels of these genes differed according to the presence or absence of abdominal obesity. Pathway analyses revealed a statistically significant contribution of the aforementioned genes to dopaminergic synapse transmission (p = 4.78E-08). Furthermore, SLC18A1 and SLC6A3 gene methylation signatures correlated with total energy (p < 0.001) and carbohydrate (p < 0.001) intakes. Conclusions: The results of this investigation reveal that methylation status on DA signaling genes may underlie epigenetic mechanisms contributing to carbohydrate and calorie consumption and fat deposition.
Autores: Goñi, Leticia; García-Granero, Marta; Milagro FI; et al.
Revista: NUTRITION AND DIABETES
ISSN 2044-4052  Vol. 8  Nº 1  2018  págs. 27
BACKGROUND/OBJECTIVE: Obesity is a complex and multifactorial disease resulting from the interactions among genetics, metabolic, behavioral, sociocultural and environmental factors. In this sense, the aim of the present study was to identify phenotype and genotype variables that could be relevant determinants of body mass index (BMI) variability. SUBJECTS/METHODS: In the present study, a total of 1050 subjects (798 females; 76%) were included. Least angle regression (LARS) analysis was used as regression model selection technique, where the dependent variable was BMI and the independent variables were age, sex, energy intake, physical activity level, and 16 polymorphisms previously related to obesity and lipid metabolism. RESULTS: The LARS analysis obtained the following formula for BMI explanation: (64.7¿+¿0.10¿×¿age [years]¿+¿0.42¿×¿gender [0, men; 1, women]¿+¿-40.6¿×¿physical activity [physical activity level]¿+¿0.004¿×¿energy intake [kcal]¿+¿0.74¿×¿rs9939609 [0 or 1-2 risk alleles]¿+¿-0.72¿×¿rs1800206 [0 or 1-2 risk alleles]¿+¿-0.86¿×¿rs1801282 [0 or 1-2 risk alleles]¿+¿0.87¿×¿rs429358 [0 or 1-2 risk alleles]. The multivariable regression model accounted for 21% of the phenotypic variance in BMI. The regression model was internally validated by the bootstrap method (r2 original data set¿=¿0.208, mean r2 bootstrap data sets¿=¿0.210). CONCLUSION: In conclusion, age, physical activity, energy intake and polymorphisms in FTO, APOE, PPARG and PPARA genes are significant predictors of the BMI trait.
Autores: Varela-Guruceaga M; Milagro FI; Martínez, JA; et al.
Revista: MOLECULAR AND CELLULAR ENDOCRINOLOGY
ISSN 0303-7207  Vol. 473  2018  págs. 257 - 267
Obesity is characterized by hypertrophy and hyperplasia of adipose tissue, which have been related to the development of hypoxia and insulin resistance. On the other hand, caveolin-1 (Cav-1), one of the main proteins of caveolae, promotes insulin receptor (IR) phosphorylation and the subsequent activation of insulin signaling. In this work we investigated the effect of hypoxia on Cav-1 regulation and the status of insulin signaling in 3T3-L1 adipocytes. Our results showed that hypoxia inhibited adipogenesis and insulin signaling in adipocytes. Furthermore, 48¿h of hypoxia reduced insulin-induced glucose uptake while increased basal glucose uptake. This result was consistent with the upregulation of glucose transporter GLUT1 and the downregulation of GLUT4, which also showed defective translocation to plasma membrane when adipocytes were stimulated with insulin. In addition, the expression of caveolae-related proteins was reduced by hypoxia and chromatin immunoprecipitation assay demonstrated that Cav-1 transcription was directly regulated by HIF-1. These results strengthen the role of caveolae in insulin signaling and help to explain adipocyte response to hypoxia.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: MOLECULAR GENETICS AND METABOLISM
ISSN 1096-7192  Vol. 123  Nº 1  2018  págs. 50 - 58
A sustained activation of the unfolded protein response and the subsequent endoplasmic reticulum (ER) stress has been involved in the onset and severity of several metabolic diseases. The aim of this study was to analyze the association of DNA methylation signatures at ER stress genes with adiposity traits and related metabolic disorders. An epigenomic analysis within the Methyl Epigenome Network Association (MENA) project was conducted in an adult population (n=474). DNA methylation status in peripheral white blood cells was analyzed by a microarray approach. KEGG database was used to the characterization and discrimination of genes involved in the "protein processing in endoplasmic reticulum pathway". Anthropometric measurements and plasma metabolic profiles were analyzed. A total of 15 CpG sites at genes participating in ER pathway were strongly correlated with BMI after adjusted linear regression analyses (p<0.0001). These included cg08188400 (MAP2K7), cg20541779 (CASP12), cg24776411 (EIF2AK1), cg14190817 (HSPA5), cg21376454 (ERN1), cg06666486 (EIF2AK1), cg03211481 (DNAJC1), cg18357645 (OS9), cg05801879 (MBTPS1), cg20964082 (ERO1LB), cg17300868 (NFE2L2), cg03384128 (EIF2AK4), cg02712587 (EIF2AK4), cg04972384 (SELS), cg02240686 (EIF2AK2). Noteworthy, most of them were implicated in ER stress (p=2.9E-09). However, only methylation levels at cg20964082 (ERO1LB), cg17300868 (NFE2L2), cg05801879 (MBTPS1), and cg03384128 (EIF2AK4) also correlated with total fat mass. Interestingly, significant associations between methylation patterns at cg20964082 (ERO1LB) and cg17300868 (NFE2L2) and insulin and HOMA-IR index were found, whereas cg05801879 (MBTPS1) and cg03384128 (EIF2AK4) were correlated with triglyceride levels. This study suggests associations of methylation signatures at ER stress genes with adiposity and insulin resistance, as revealed by discriminative pathway analyses.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: NUTRITION
ISSN 0899-9007  Vol. 47  2018  págs. 83 - 89
Objectives: The aim of this study was to investigate the influence of two PPARGCIA gene polymorphisms on metabolic outcomes in response to two energy-restricted diets. Methods: A 4-mo nutritional intervention was conducted that involved two different hypo-energetic diets based on low-fat (LF) and moderately high-protein (MHP) dietary patterns. Unrelated subjects with excessive weight were genotyped for two PPARGCIA polymorphisms: Rs8192678 (Gly482Ser) and rs3755863 (G > A). Genotyping was performed by next-generation sequencing and haplotypes were screened. Anthropometric measurements and biochemical tests were assessed with standardized methods. Results: Different cholesterol outcomes were observed by diet and Gly482Ser genotype. The Gly482 Gly homozygotes after an LF diet had lower reductions in total cholesterol (-9 mg/dL vs. -27 mg/dL; P = 0.017) and low-density lipoprotein cholesterol levels (-5 mg/dL vs. -18 mg/dL; P = 0.016) than the subjects who were carriers of 482 Ser allele. However, this finding was not recorded in the MHP group where Gly482 Gly homozygotes underwent similar cholesterol decreases as the 482 Ser allele carriers. Likewise, all genotype carriers had significant reductions in the frequencies of hypercholesterolemia (total cholesterol >= 200 mg/dL) except for Gly482 Gly homozygotes in the LF group. Meanwhile, the rs3755863 polymorphism and PPARGCIA haplotypes showed borderline effects with regard to cholesterol decreases. Conclusions: An energy-restricted MHP diet might be more beneficial than an LF diet to reduce serum cholesterol among subjects who are carriers of the PPARGCIA Gly482Gly genotype. The analysis of this genetic variant might be the basis for a precise. nutrigenetic management of hypercholesterolemia based on genetic makeup.
Autores: García, Marcos; Martínez, JA, (Autor de correspondencia); Zulet, María de los Ángeles; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 13  Nº 8  2018 
Background Non-coding RNAs (i.e., miRNAs) play a role in the development of obesity and related comorbidities and the regulation of body weight. Objective To identify candidate miRNA biomarkers throughout omics approaches in order to predict the response to specific weight-loss dietary treatments. Design Genomic DNA and cDNA isolated from white blood cells of a subset from the RESMENA nutritional intervention study (Low-responders (LR) vs High-responders (HR)) was hybridized in Infinium Human Methylation450 BeadChip and in Illumina Human HT-12 v4 gene expression BeadChips arrays respectively. A bioinformatic prediction of putative target sites of selected miRNAs was performed by applying miRBase algorithms. HEK-293T cells were co-transfected with expression vectors containing the 3'-UTR of candidate genes to validate the binding of miRNAs to its target sites. Results 134 miRNAs were differentially methylated between HR and LR in the methylation array, whereas 44 miRNAs were differentially expressed between both groups in the expression array. Specifically, miR-1237, miR-1976, miR-642, miR-636, miR-612 and miR-193B were simultaneously hypomethylated and overexpressed in HR. miR-612 and miR-1976 showed greatest differences in methylation and expression levels, respectively. The bioinformatic prediction revealed that TP53 was a putative target gene of miR-612 and CD40 of miR-1976. Moreover, TP53 was downregulated in the expression array when comparing HR vs LR expression levels adjusted by sex, diet, age and baseline weight, and CD40 showed a statistical trend. Furthermore, gene expression levels of TP53 and CD40 in white blood cells, when measured by qPCR, were also downregulated in HR. Finally, miR-612 and miR-1976 potently repressed TP53 and CD40 respectively by targeting its 3'-UTR regions. Conclusion miR-612 and miR-1976 levels could be prospective biomarkers of response to specific weight-loss diets and might regulate the gene expression of TP53 and CD40.
Autores: Milton-Laskibar, I.; Aguirre, L., (Autor de correspondencia); Etxeberria, Usune; et al.
Revista: FOOD & FUNCTION
ISSN 2042-6496  Vol. 9  Nº 8  2018  págs. 4207 - 4215
Autophagy eliminates damaged cellular components. In the liver, it has been proposed that it mediates the breakdown of lipid droplets. This study aimed to compare the involvement of autophagy and the oxidative status in the effects of resveratrol and energy restriction as therapeutic tools for managing liver steatosis. In addition, potential additive or synergic effects were studied. Rats were fed a high-fat high-sucrose diet for 6 weeks and then divided into four experimental groups and fed a standard diet: a control group (C), a resveratrol-treated group (RSV, 30 mg kg(-1) d(-1)), an energy restricted group (R, -15%), and an energy restricted group treated with resveratrol (RR). Liver triacylglycerols (TGs) were measured by Folch's method. TBARS, GSH, GSSG, GPx and SOD were assessed using commercial kits. The protein expression of beclin, atg5 and p62, as well as ratios of pSer555 ULK1/total ULK1, pSer757 ULK1/total ULK1 and LC3 II/I were determined by western blotting. Energy restriction increased the protein expression of beclin, atg5 and pSer757 ULK1/total ULK1 and LC3 II/I ratios, and reduced the protein expression of p62, thus indicating that it induced autophagy activation. The effects of resveratrol were similar but less marked than the hypocaloric diet. No differences were observed in oxidative stress determinants except for TBARS, which was decreased by energy restriction. In conclusion, resveratrol can reverse partially dietary-induced hepatic lipid accumulation, although less efficiently than energy restriction. The delipidating effect of energy restriction is mediated in part by the activation of autophagy; however, the involvement of this process in the effects of resveratrol is less clear.
Autores: Milagro FI; Mansego, Maria L; et al.
Revista: PEDIATRIC OBESITY
ISSN 2047-6310  Vol. 13  Nº 3  2018  págs. 149 - 158
BackgroundThe global prevalence of childhood overweight and obesity has increased in the last years. Epigenetic dysregulation affecting gene expression could be a determinant in early-life obesity onset and accompanying complications. ObjectiveThe aim of the present investigation was to analyse the putative association between DNA methylation and childhood obesity. MethodsDNA was isolated from white blood cells of 24 children obtained from the GENOI study and was hybridized in a 450K methylation array. Two CpG sites associated with obesity were validated in 91 children by MassArray (R) EpiTyper technology. ResultsGenome-wide analysis identified 734 CpGs (783 genes) differentially methylated between cases (n=12) and controls (n=12). Ingenuity Pathway Analysis showed that these genes were involved in oxidative stress and circadian rhythm signalling pathways. Moreover, the DNA methylation levels of VIPR2, GRIN2D, ADCYAP1R1, PER3 and PTPRS regions correlated with the obesity trait. EpiTyper validation also identified significant correlations between methylation levels of CpG sites on PTPRS and PER3 with BMI z-score. ConclusionsThis study identified several CpG sites and specifically several CpGs in the PTPRS and PER3 genes differentially methylated between obese and non-obese children, suggesting a role for DNA methylation concerning development of childhood obesity.
Autores: Ramos-López, O.; Milagro FI; et al.
Revista: CHRONOBIOLOGY INTERNATIONAL
ISSN 1525-6073  Vol. 35  Nº 7  2018  págs. 969-981
Autores: De Silva, N.; Martínez, JA; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 74  Nº 4  2018  págs. 559-568
Obesity is usually associated with low-grade inflammation, which determines the appearance of comorbidities like atherosclerosis and insulin resistance. Infiltrated macrophages in adipose tissue are partly responsible of this inflammatory condition. Numerous studies point to the existence of close intercommunication between macrophages and adipocytes and pay particular attention to the proinflammatory cytokines released by both cell types. However, it has been recently described that in both, circulation and tissue level, there are extracellular vesicles (including microvesicles and exosomes) containing miRNAs, mRNAs, and proteins that can influence the inflammatory response. The objective of the present research is to investigate the effect of exosomes released by lipopolysaccharide (LPS)-activated macrophages on gene expression and cell metabolism of adipocytes, focusing on the differential exosomal miRNA pattern between LPS- and non-activated macrophages. The results show that the exosomes secreted by the macrophages do not influence the preadipocyte-to-adipocyte differentiation process, fat storage, and insulin-mediated glucose uptake in adipocytes. However, exosomes induce changes in adipocyte gene expression depending on their origin (LPS- or non-activated macrophages), including genes such as CXCL5, SOD, TNFAIP3, C3, and CD34. Some of the pathways or metabolic processes upregulated by exosomes from LPS-activated macrophages are related to inflammation (complement activation, regulation of reactive oxygen species, migration and activation of leukocyte, and monocyte chemotaxis), carbohydrate catabolism, and cell activation. miR-530, chr9_22532, and chr16_34840 are more abundant in exosomes from LPS-activated macrophages, whereas miR-127, miR-143, and miR-486 are more abundant in those secreted by non-activated macrophages.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES
ISSN 0939-4753  Vol. 28  Nº 2  2018  págs. 165 - 172
BACKGROUND AND AIMS: A precise nutrigenetic management of hypercholesterolemia involves the understanding of the interactions between the individual's genotype and dietary intake. The aim of this study was to analyze the response to two dietary energy-restricted interventions on cholesterol changes in carriers of two ADRB2 polymorphisms. METHODS AND RESULTS: A 4-month nutritional intervention was conducted involving two different hypo-energetic diets based on low-fat (LF) and moderately high-protein (MHP) dietary patterns. A total of 107 unrelated overweight/obese individuals were genotyped for two ADRB2 non-synonymous polymorphisms: Arg16Gly (rs1042713) and Gln27Glu (rs1042714). Genotyping was performed by next-generation sequencing and haplotypes were phenotypically screened. Anthropometric measurements and the biochemical profile were assessed by conventional methods. Both diets induced cholesterol decreases at the end of both nutritional interventions. Interestingly, phenotypical differences were observed according to the Arg16Gly polymorphism. Within the MHP group, Gly16Gly homozygotes had lower reductions in total cholesterol (-6.5 mg/dL vs. -24.2 mg/dL, p = 0.009), LDL-c levels (-1.4 mg/dL vs. -16.5 mg/dL, p = 0.005), and non-HDL-c (-4.5 mg/dL vs. -21.5 mg/dL, p = 0.008) than Arg16 allele carriers. Conversely, within the LF group, Gly16Gly homozygotes underwent similar falls in total cholesterol (-18.5 mg/dL vs. -18.7 mg/dL, ns), LDL-c levels (-9.7 mg/dL vs. -13.1 mg/dL, ns), and non-HDL-c (-15.3 mg/dL vs. -15.7 mg/dL, ns) than Arg16 allele carriers. The Gln27Glu polymorphism and the Gly16/Glu27 haplotype showed similar, but not greater effects. CONCLUSIONS: An energy-restricted LF diet could be more beneficial than a MHP diet to reduce serum cholesterol, LDL-c, and non-HDL-c among Gly16Gly genotype carriers. CLINICALTRIALS.GOV: Identifier: NCT02737267.
Autores: Milton-Laskibar, I.; Aguirre, L. , (Autor de correspondencia); Etxeberria, U.; et al.
Revista: NUTRIENTS
ISSN 2072-6643  Vol. 10  Nº 10  2018 
The aim of this study was to compare the effects of mild energy restriction and resveratrol on thermogenic and oxidative capacity in interscapular brown adipose tissue (IBAT) and in skeletal muscle. Rats were fed a high-fat high-sucrose diet for six weeks, and divided into four experimental groups fed a standard diet: a control group, a resveratrol-treated group, an energy-restricted group and an energy-restricted group treated with resveratrol. Weights of IBAT, gastrocnemius muscle and fat depots were measured. Activities of carnitine palmitoyltransferase (CPT) and citrate synthase (CS), protein levels of sirtuin (SIRT1 and 3), uncoupling proteins (UCP1 and 3), glucose transporter (GLUT4), mitochondrial transcription factor (TFAM), nuclear respiratory factor (NRF1), peroxisome proliferator-activated receptor (PPAR) and AMP activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator (PGC1) activation were measured. No changes in IBAT and gastrocnemius weights were found. Energy-restriction, but not resveratrol, decreased the weights of adipose depots. In IBAT, resveratrol enhanced thermogenesis activating the SIRT1/PGC1/PPAR axis. Resveratrol also induced fatty acid oxidation and glucose uptake. These effects were similar when resveratrol was combined with energy restriction. In the case of gastrocnemius muscle, the effects were not as clear as in the case of IBAT. In this tissue, resveratrol increased oxidative capacity. The combination of resveratrol and energy restriction seemingly did not improve the effects induced by the polyphenol alone.
Autores: Ramos-Lopez, O.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: INTERNATIONAL JOURNAL OF GENOMICS
ISSN 2314-436X  2018 
Background and Aim. Individual lipid phenotypes including circulating total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), and triglycerides (TG) determinations are influenced by gene-environment interactions. The aim of this study was to predict blood lipid level (TC, LDL-c, HDL-c, and TG) variability using genetic and lifestyle data in subjects with excessive body weight-for-height. Methods. This cross-sectional study enrolled 304 unrelated overweight/obese adults of self-reported European ancestry. A total of 95 single nucleotide polymorphisms (SNPs) related to obesity and weight loss were analyzed by a targeted next-generation sequencing system. Relevant genotypes of each SNP were coded as 0 (nonrisk) and 1 (risk). Four genetic risk scores (GRS) for each lipid phenotype were calculated by adding the risk genotypes. Information concerning lifestyle (diet, physical activity, alcohol drinking, and smoking) was obtained using validated questionnaires. Total body fat (TFAT) and visceral fat (VFAT) were determined by dual-energy X-ray absorptiometry. Results. Overall, 45 obesity-related genetic variants were associated with some of the studied blood lipids. In addition to conventional factors (age, sex, dietary intakes, and alcohol consumption), the calculated GRS significantly contributed to explain their corresponding plasma lipid trait. Thus, HDL-c, TG, TC, and LDL-c serum concentrations were predicted by approximately 28% (optimism-corrected adj. R-2 = 0 28), 25% (optimism-corrected adj. R-2 = 0 25), 24% (optimism-corrected adj. R-2 = 0 24), and 21% (optimism-corrected adj. R-2 = 0.21), respectively. Interestingly, GRS were the greatest contributors to TC (squared partial correlation (PC2) = 0.18) and LDL-c (PC2 = 0.18) features. Likewise, VFAT and GRS had a higher impact on HDL-c (PC2 = 0.09 and PC2 = 0.06, respectively) and TG levels (PC2 = 0.20 and PC2 = 0.07, respectively) than the rest of variables. Conclusions. Besides known lifestyle influences, some obesity-related genetic variants could help to predict blood lipid phenotypes.
Autores: Marques-Rocha, J. L.; García, Marcos; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 74  Nº 4  2018  págs. 579 - 589
The main aim of this investigation was to study the regulatory roles of let-7b and miR-155-3p on the expression of inflammation-associated genes in monocytes, macrophages, and lipopolysaccharide (LPS)-activated macrophages (AcM). A second goal was to analyze the potential modulatory roles of different fatty acids, including oleic, palmitic, eicosapentaenoic (EPA), and docosahexaenoic (DHA), on the expression of these miRNAs in the three cell types. This hypothesis was tested in human acute monocytic leukemia cells (THP-1), which were differentiated into macrophages with 2-O-tetradecanoylphorbol-13-acetate (TPA) and further activated with LPS for 24h. Monocytes, macrophages, and AcM were transfected with a negative control, or mimics for miR-155-3p and miR-let-7b-5p. The expression of both miRNAs and some proinflammatory genes was analyzed by qRT-PCR. Interestingly, let-7b mimic reduced the expression of IL6 and TNF in monocytes, and SERPINE1 expression in LPS-activated macrophages. However, IL6, TNF, and SERPINE1 were upregulated in macrophages by let-7b mimic. IL6 expression was higher in the three types of cells after transfecting with miR-155-3p mimic. Similarly, expression of SERPINE1 was increased by miR-155-3p mimic in monocytes and macrophages. However, TLR4 was downregulated by miR-155-3p in monocytes and macrophages. Regarding the effects of the different fatty acids, oleic acid increased the expression of let-7b in macrophages and AcM and also increased the expression of miR-155 in monocytes when compared with DHA but not when compared with non-treated cells. Overall, these results suggest anti- and proinflammatory roles of let-7b and miR-155-3p in THP-1 cells, respectively, although these outcomes are strongly dependent on the cell type. Noteworthy, oleic acid might exert beneficial anti-inflammatory effects in immune cells (i.e., non-activated and LPS-activated macrophages) by upregulating the expression of let-7b.
Autores: Arpon, A.; Milagro FI; Laja, A.; et al.
Revista: EPIGENOMICS
ISSN 1750-1911  Vol. 10  Nº 1  2018  págs. 91 - 103
Aim: To analyze whether preterm newborns show differences in methylation patterns in comparison to full-term newborns in white blood cells. Patients & methods: Anthropometrical, biochemical features and methylation levels of preterm newborns (n = 24) and full-term newborns (n = 22) recruited in La Paz University Hospital (Spain) were assessed at 12 months of gestational age, whereas Bayley Scale of Infant Development was evaluated at 24/36 months. Results: From all the statistically significant CpGs, methylation levels of cg00997378 (SLC6A3 gene) showed the highest differences (p < 0.0001), being associated with prematurity risk factors. Conclusion: SLC6A3 methylation, previously related to attention-deficit/hyperactivity disorder, neuronal function and behavior, might be a potential epigenetic biomarker with value in the early diagnosis and management of neurodevelopmental diseases in newborns.
Autores: Goñi, Leticia; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: NUTRIENTS
ISSN 2072-6643  Vol. 10  Nº 6  2018  págs. E789
The adenylate cyclase 3 (ADCY3) gene is involved in the regulation of several metabolic processes including the development and function of adipose tissue. The effects of the ADCY3 rs10182181 genetic variant on changes in body composition depending on the macronutrient distribution intake after 16 weeks of the dietary intervention were tested. The ADCY3 genetic variant was genotyped in 147 overweight or obese subjects, who were randomly assigned to one of the two diets varying in macronutrient content: a moderately-high-protein diet and a low-fat diet. Anthropometric and body composition measurements (DEXA scan) were recorded. Significant interactions between the ADCY3 genotype and dietary intervention on changes in weight, waist circumference, and body composition were found after adjustment for covariates. Thus, in the moderately-high-protein diet group, the G allele was associated with a lower decrease of fat mass, trunk and android fat, and a greater decrease in lean mass. Conversely, in the low-fat diet group carrying the G allele was associated with a greater decrease in trunk, android, gynoid, and visceral fat. Subjects carrying the G allele of the rs10182181 polymorphism may benefit more in terms of weight loss and improvement of body composition measurements when undertaking a hypocaloric low-fat diet as compared to a moderately-high-protein diet.
Autores: Milton-Laskibar, I. ; Aguirre, L. ; Romo, N. ; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 73  Nº Supl. 2  2018  págs. 59 - 59
Autores: Martínez, JA; García, Marcos; Astrom, G.; et al.
Revista: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN 0014-2972  Vol. 48  Nº Supl. 1  2018  págs. 196 - 196
Autores: Ramos-Lopez, O. ; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN 0014-2972  Vol. 48  Nº Supl. 1  2018  págs. 40 - 41
Autores: Martínez, JA; Milagro FI;
Revista: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN 0014-2972  Vol. 48  Nº Supl. 1  2018  págs. 208 - 208
Autores: Milton-Laskibar, I.; Aguirre, L. ; Etxeberria, Usune; et al.
Revista: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN 0014-2972  Vol. 48  Nº Supl. 1  2018  págs. 181
Autores: Solas, Maite; Milagro FI; Ramírez, M.J.; et al.
Revista: CURRENT OPINION IN PHARMACOLOGY
ISSN 1471-4892  Vol. 37  2017  págs. 87 - 92
Obesity prevalence is increasing steadily throughout the world's population in most countries and in parallel the prevalence of metabolic disorders including cardiovascular diseases and type 2 diabetes is also rising, but less is reported about excessive adiposity relationship with poorer cognitive performance, cognitive decline and dementia. Some human clinical studies have evidenced that obesity is related to the risk of the development of mild cognitive impairment, in the form of short-term memory and executive function deficits, as well as dementia and Alzheimer's disease. The precise mechanisms that underlie the connections between obesity and the risk of cognitive impairment are still largely unknown but potential avenues of further research include insulin resistance, the gut brain axis, and systemic mediators and central inflammation processes. A common feature of metabolic diseases is a chronic and low-grade activation of the inflammatory system. This inflammation may eventually spread from peripheral tissue to the brain, and recent reports suggest that neuroinflammation is an important causal mechanism in cognitive decline. This inflammatory status could be triggered by changes in the gut microbiota composition. Consumption of diets high in fat and sugar influences the microbiota composition, which may lead to an imbalanced microbial population in the gut. Thus, it has recently been hypothesized that the gut microbiota could be part of a mechanistic link between the consumption of high fat and other unbalanced diets and impaired cognition, termed 'gut-brain axis'. The present review will aim at providing an integrative analysis of the effects of obesity and unbalanced diets on cognitive performance and discusses some of the potential mechanisms involved, namely inflammation and changes in gut-brain axis. Moreover, the review aims to analyze anti-inflammatory drugs that have been tested for the treatment of cognition and obesity, recently approved anti-obesity drugs that could also have an impact on central nervous system, and bioactive food compounds that modulate gut microbiota and could have an impact through the gut-brain axis. In this era of precision nutrition medicine, it is imperative to identify the various metabolic-neurocognitive phenotypes in order to understand the processes that drive these diseases so that targeted therapeutic strategies to prevent and successfully manage these complex, multifactorial diseases could be designed and developed.
Autores: Ramos-Lopez, O.; Milagro FI; Allayee, H.; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 10  Nº 1 - 2  2017  págs. 43 - 62
Chronic diseases, including obesity, are major causes of morbidity and mortality in most countries. The adverse impacts of obesity and associated comorbidities on health remain a major concern due to the lack of effective interventions for prevention and management. Precision nutrition is an emerging therapeutic approach that takes into account an individual's genetic and epigenetic information, as well as age, gender, or particular physiopathological status. Advances in genomic sciences are contributing to a better understanding of the role of genetic variants and epigenetic signatures as well as gene expression patterns in the development of diverse chronic conditions, and how they may modify therapeutic responses. This knowledge has led to the search for genetic and epigenetic biomarkers to predict the risk of developing chronic diseases and personalizing their prevention and treatment. Additionally, original nutritional interventions based on nutrients and bioactive dietary compounds that can modify epigenetic marks and gene expression have been implemented. Although caution must be exercised, these scientific insights are paving the way for the design of innovative strategies for the control of chronic diseases accompanying obesity. This document provides a number of examples of the huge potential of understanding nutrigenetic, nutrigenomic, and nutriepigenetic roles in precision nutrition.
Autores: Crujeiras, Ana Belén; Diaz-Lagares, A.; Sandoval, J.; et al.
Revista: SCIENTIFIC REPORTS
ISSN 2045-2322  Vol. 7  2017  págs. 41903
The characterization of the epigenetic changes within the obesity-related adipose tissue will provide new insights to understand this metabolic disorder, but adipose tissue is not easy to sample in population-based studies. We aimed to evaluate the capacity of circulating leukocytes to reflect the adipose tissue-specific DNA methylation status of obesity susceptibility. DNA samples isolated from subcutaneous adipose tissue and circulating leukocytes were hybridized in the Infinium HumanMethylation 450 BeadChip. Data were compared between samples from obese (n¿=¿45) and non-obese (n¿=¿8-10) patients by Wilcoxon-rank test, unadjusted for cell type distributions. A global hypomethylation of the differentially methylated CpG sites (DMCpGs) was observed in the obese subcutaneous adipose tissue and leukocytes. The overlap analysis yielded a number of genes mapped by the common DMCpGs that were identified to reflect the obesity state in the leukocytes. Specifically, the methylation levels of FGFRL1, NCAPH2, PNKD and SMAD3 exhibited excellent and statistically significant efficiencies in the discrimination of obesity from non-obesity status (AUC¿>¿0.80; p¿<¿0.05) and a great correlation between both tissues. Therefore, the current study provided new and valuable DNA methylation biomarkers of obesity-related adipose tissue pathogenesis through peripheral blood analysis, an easily accessible and minimally invasive biological material instead of adipose tissue.
Autores: Huerta, Ana Elsa; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: JOURNAL OF FUNCTIONAL FOODS
ISSN 1756-4646  Vol. 36  2017  págs. 178 - 185
This study aims to assess methylation modifications in blood cell genes induced by eicosapentaenoic acid (EPA) and/or alpha-lipoic acid (LA) supplementation, and their potential relationship with metabolic risk biomarkers. Healthy overweight/obese women were assigned to 4 experimental groups (control or groups supplemented with 1.3 g EPA/day, 0.3 g LA/day, or both), all followed a 10-week hypocaloric diet. White blood cells DNA was hybridized in Human-450K-methylation microarray. Differentially methylated CpGs (post-pre) were identified in supplemented groups, including CpG regions from NCK2, FITM2, TRRAP, RPTOR and CREBBP genes. In peripheral blood mononuclear cells (PBMC), LA upregulated NCK2, TRRAP and RPTOR mRNA, which negatively associated with changes in body weight and fat mass. Changes in cg10320884 (TRRAP) methylation site negatively correlated with changes in TRRAP mRNA in PBMC, and positively with Framingham score. Further studies are needed to better characterize the potential involvement of epigenetics in the actions of LA and EPA.
Autores: Ramos-Lopez, O.; Arpón, A.; Riezu-Boj, José Ignacio; et al.
Revista: APPETITE
ISSN 0195-6663  Vol. 120  2017  págs. 230 - 239
Individual differences in taste perception may influence appetite, dietary intakes, and subsequently, disease risk. Correlations of DNA methylation patterns at taste transducing genes with BMI and dietary intakes were studied. A nutriepigenomic analysis within the Methyl Epigenome Network Association (MENA) project was conducted in 474 adults. DNA methylation in peripheral white blood cells was analyzed by a microarray approach. KEGG pathway analyses were performed concerning the characterization and discrimination of genes involved in the taste transduction pathway. Adjusted FDR values (p < 0.0001) were used to select those CpGs that showed best correlation with BMI. A total of 29 CpGs at taste transducing genes met the FDR criteria. However, only 12 CpGs remained statistically significant after linear regression analyses adjusted for age and sex. These included cg15743657 (TAS1R2), cg02743674 (TRPM5), cg01790523 (SCN9A), cg15947487 (CALHM1), cg11658986 (ADCY6), cg04149773 (ADCY6), cg02841941 (P2RY1), cg02315111 (P2RX2), cg08273233 (HTR1E), cg14523238 (GABBR2), cg12315353 (GABBR1) and cg05579652 (CACNA1C). Interestingly, most of them were implicated in the sweet taste signaling pathway, except CACNA1C (sour taste). In addition, TAS1R2 methylation at cg15743657 was strongly correlated with total energy (p < 0.0001) and carbohydrate intakes (p < 0.0001). This study suggests that methylation in genes related to sweet taste could be an epigenetic mechanism associated with obesity.
Autores: Milton-Laskibar, I.; Aguirre, L.; Macarulla, M. T.; et al.
Revista: BIOFACTORS
ISSN 0951-6433  Vol. 43  Nº 3  2017  págs. 371 - 378
Resveratrol (RSV) has been proposed as an energy restriction mimetic. This study aimed to compare the effects of RSV and energy restriction on insulin resistance induced by an obesogenic diet. Any additive effect of both treatments was also analyzed. Rats were fed a high-fat high-sucrose diet for 6 weeks. They were then distributed in four experimental groups which were either fed a standard control diet (C), or treated with RSV (30 mg/kg/d), or submitted to energy restriction (R, 15%), or treated with RSV and submitted to energy restriction (RR). A glucose tolerance test was performed, and serum glucose, insulin, fructosamine, adiponectin, and leptin concentrations determined. Muscle triacylglycerol content and protein expression of insulin receptor (IRß), protein kinase B (Akt), Akt substrate of 160 kDa (AS160) and glucose transporter 4 (GLUT-4) were measured. In RSV rats, fructosamine concentrations were reduced, HOMA-IR remained unchanged, but glucose tolerance was improved, without changes in phosphorylation of IRß, Akt, and AS160 or in GLUT-4 protein expression. Rats under energy restriction showed an improvement in all the markers related to glycemic control, as well as increased phosphorylation of AS160 and protein expression of GLUT-4. In rats from RR group the results were similar to R group, with the exception of IRß and Akt phosphorylation, which were increased. In conclusion, mild energy restriction is more efficient than intake of RSV within a standard balanced diet, and acts by means of a different mechanism from that of RSV. No additive effects between RSV and energy restriction were observed.
Autores: Bengoetxea, Xabier; Martisova, E.; et al.
Revista: JOURNAL OF PSYCHOPHARMACOLOGY
ISSN 0269-8811  Vol. 31  Nº 3  2017  págs. 356 - 364
The present work studies whether chronic prenatal stress (PS) influences the long-term sex-dependent neuropsychological status of offspring and the effects of an early dietary intervention in the dam. In addition, dams were fed with either a high-fat sugar diet (HFSD) or methyl donor supplemented diet (MDSD). PS procedure did not affect body weight of the offspring. MDSD induced decreases in body weight both in male and female offspring (1 month) that were still present in aged rats. HFSD induced an increase in body weight both in male and female offspring that did not persist in aged rats. In the Porsolt forced swimming test, only young males showed increases in immobility time that were reversed by MDSD. In old female rats (20 months), PS-induced cognitive impairment in both the novel object recognition test (NORT) and in the Morris water maze that was reversed by MDSD, whereas in old males, cognitive impairments and reversion by MDSD was evident only in the Morris water maze. HFSD induced cognitive impairment in both control and PS old rats, but there was no additive effect of PS and HFSD. It is proposed here that the diversity of symptoms following PS could arise from programming effects in early brain development and that these effects could be modified by dietary intake of the dam.
Autores: Aranaz, Paula; Romo, Ana; et al.
Revista: FOOD & FUNCTION
ISSN 2042-6496  2017 
Obesity and type 2-diabetes are becoming a worldwide health problem, remarking the importance of alternative therapies to tackle their progression. Here, we hypothesized that supplementation of diet with 6 % w/w of a freeze-dried strawberry-blueberry (5:1) powder (FDSB) could exert beneficial metabolic effects in Wistar rats. FDSB-supplemented animals experienced significantly reduced body weight gain, food efficiency and visceral adiposity accumulation in two independent experiments. FDSB supplementation also contributed to lower area under the curve after an intraperitoneal GTT and reduced serum insulin levels and insulin resistance index (IR-HOMA) in HFS diet-fed animals, together with reduced plasma MCP-1 inflammation marker concentrations. Gene expression analysis in retroperitoneal adipocytes from experiment 1 and 3T3-L1 cells showed that FDSB inhibited adipogenesis and lipogenesis through down-regulation of Pparg, Cebpa, Lep, Fasn, Scd-1 and Lpl gene expression. Untargeted metabolomics identified the cis isomer ofresveratrol-3-glucoside-sulphate as a metabolite differentially increased in FDSB-treated serum samples, which corresponds to a strawberry metabolite that could be considered a serum biomarker of FDSB-intake. Our results suggest that FDSB powder might be useful for treatment/prevention of obesity-related diseases.
Autores: Huerta, Ana Elsa; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: JOURNAL OF FUNCTIONAL FOODS
ISSN 1756-4646  Vol. 36  2017  págs. 178 - 185
This study aims to assess methylation modifications in blood cell genes induced by eicosapentaenoic acid (EPA) and/or alpha-lipoic acid (LA) supplementation, and their potential relationship with metabolic risk biomarkers. Healthy overweight/obese women were assigned to 4 experimental groups (control or groups supplemented with 1.3 g EPA/day, 0.3 g LA/day, or both), all followed a 10-week hypocaloric diet. White blood cells DNA was hybridized in Human-450K-methylation microarray. Differentially methylated CpGs (post-pre) were identified in supplemented groups, including CpG regions from NCK2, FITM2, TRRAP, RPTOR and CREBBP genes. In peripheral blood mononuclear cells (PBMC), LA upregulated NCK2, TRRAP and RPTOR mRNA, which negatively associated with changes in body weight and fat mass. Changes in cg10320884 (TRRAP) methylation site negatively correlated with changes in TRRAP mRNA in PBMC, and positively with Framingham score. Further studies are needed to better characterize the potential involvement of epigenetics in the actions of LA and EPA. (C) 2017 Elsevier Ltd. All rights reserved.
Autores: Ramos-Lopez, O.; Samblas, M.; Milagro FI; et al.
Revista: NUTRITION RESEARCH
ISSN 0271-5317  Vol. 50  2017  págs. 53 - 62
Folate deficiency has been putatively implicated in the onset of diverse metabolic abnormalities, including insulin resistance, by altering epigenetic processes on key regulatory genes. The calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is involved in the regulation of critical metabolic processes such as adiposity and glucose homeostasis. This study hypothesized associations between low folate intakes and lower methylation levels of the CAMKK2 gene, with the presence of metabolic alterations in subjects with obesity. A cross-sectional ancillary study was conducted in obese subjects (n=47) from the RESMENA study (Spain). Fat mass was measured by dual-energy x-ray absorptiometry. Dietary intake and metabolic profile were assessed by validated methods. DNA methylation and gene expression in peripheral white blood cells were analyzed by microarray approaches. A total of 51 cytosine-phosphate-guanine sites were associated with folate intake (false discovery rate values < 0.0001), including one located in the 5' untranslated region of the CAMKK2 gene (Illumina ID, cg16942632), which was selected and separately analyzed. Subjects with total folate intake lower than 300¿g/d showed more fat mass (especially trunk fat), as well as statistically higher levels of glucose, insulin, homeostatic model assessment-insulin resistance (HOMA-IR) index, cortisol, and plasminogen activator inhibitor-1 than those consuming at least or more than 300¿g/d. Of note, folate deficiency was related to lower CAMKK2 methylation. Interestingly, CAMKK2 methylation negatively correlated with the HOMA-IR index. Furthermore, CAMKK2 expression directly correlated with HOMA-IR values. In summary, this study suggests associations between low folate intakes, lower CAMKK2 gene methylation, and insulin resistance in obese individuals.
Autores: Goñi, Leticia; Qi, L.; Cuervo, M; et al.
Revista: AMERICAN JOURNAL OF CLINICAL NUTRITION
ISSN 0002-9165  Vol. 106  Nº 3  2017  págs. 902 - 908
Background: Circulating branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) have been shown to be associated with insulin resistance and diabetes risk. The common rs1440581 T allele in the protein phosphatase Mg2+/Mn2+ dependent 1K (PPM1K) gene has been related to elevated BCAA concentrations and risk of type 2 diabetes. Objective: In the present study, we tested whether dietary fat and carbohydrate intakes influenced the association between the rs1440581 PPM1K genetic variant and glucose-metabolism traits during weight loss. Design: The rs1440581 PPM1K genetic variant was genotyped in a total of 757 nondiabetic individuals who were randomly assigned to 1 of 2 energy-restricted diets that differed in macronutrient composition (low-fat diet: 20¿25% fat, 15% protein, and 60¿65% carbohydrate; high-fat diet: 40¿45% fat, 15% protein, and 40¿45% carbohydrate). The changes in fasting glucose, fasting insulin, insulin resistance (homeostasis model assessment of insulin resistance) and homeostasis model assessment of ß cell function (HOMA-B) were measured after a mean ± SD weight loss of 6.8 ± 3.4 kg over 10 wk and analyzed according to the presence of the T allele of rs1440581. Results: The rs1440581 T allele was associated with a smaller improvement in glucose concentrations after the 10-wk dietary intervention (ß ± SE: 0.05 ± 0.02 mg/dL; P = 0.03). In addition, significant gene-diet interactions were shown for the rs1440581 PPM1K genetic variant in relation to changes in insulin and HOMA-B (P-interaction = 0.006 and 0.002, respectively). In response to the high-fat diet, the T allele was associated with a higher reduction of insulin (ß ± SE: ¿0.77 ± 0.40 ¿U/mL; P = 0.04) and HOMA-B (ß ± SE: ¿13.2 ± 3.81; P = 0.003). An opposite effect was observed in the low-fat diet group, although in this group the T allele was marginally (P = 0.10) and not significantly (P = 0.24) associated with insulin and HOMA-B, respectively. Conclusion:PPM1K rs1440581 may affect changes in glucose metabolism during weight loss, and this effect is dependent on dietary fat and carbohydrate intakes. This trial was registered at controlled-trials.com as ISRCTN25867281.
Autores: Grimaldi, K. A. ; van Ommen, B. ; Ordovas, J. M. ; et al.
Revista: GENES AND NUTRITION
ISSN 1555-8932  Vol. 12  2017  págs. 35
Nutrigenetic research examines the effects of inter-individual differences in genotype on responses to nutrients and other food components, in the context of health and of nutrient requirements. A practical application of nutrigenetics is the use of personal genetic information to guide recommendations for dietary choices that are more efficacious at the individual or genetic subgroup level relative to generic dietary advice. Nutrigenetics is unregulated, with no defined standards, beyond some commercially adopted codes of practice. Only a few official nutrition-related professional bodies have embraced the subject, and, consequently, there is a lack of educational resources or guidance for implementation of the outcomes of nutrigenetic research. To avoid misuse and to protect the public, personalised nutrigenetic advice and information should be based on clear evidence of validity grounded in a careful and defensible interpretation of outcomes from nutrigenetic research studies. Evidence requirements are clearly stated and assessed within the context of state-of-the-art 'evidence-based nutrition'. We have developed and present here a draft framework that can be used to assess the strength of the evidence for scientific validity of nutrigenetic knowledge and whether 'actionable'. In addition, we propose that this framework be used as the basis for developing transparent and scientifically sound advice to the public based on nutrigenetic tests. We feel that although this area is still in its infancy, minimal guidelines are required. Though these guidelines are based on semi-quantitative data, they should stimulate debate on their utility. This framework will be revised biennially, as knowledge on the subject increases.
Autores: Mansego, Maria L; García, Marcos; Milagro FI; et al.
Revista: PEDIATRIC OBESITY
ISSN 2047-6310  Vol. 12  Nº 1  2017  págs. 19 - 27
BACKGROUND: Epigenetic mechanisms may be involved in obesity onset and its consequences. The aim of the present study was to evaluate whether DNA methylation status in microRNA (miRNA) coding regions is associated with childhood obesity. MATERIAL AND METHODS: DNA isolated from white blood cells of 24 children (identification sample: 12 obese and 12 non-obese) from the Grupo Navarro de Obesidad Infantil study was hybridized in a 450¿K methylation microarray. Several CpGs whose DNA methylation levels were statistically different between obese and non-obese were validated by MassArray® in 95 children (validation sample) from the same study. RESULTS: Microarray analysis identified 16 differentially methylated CpGs between both groups (6 hypermethylated and 10 hypomethylated). DNA methylation levels in miR-1203, miR-412 and miR-216A coding regions significantly correlated with body mass index standard deviation score (BMI-SDS) and explained up to 40% of the variation of BMI-SDS. The network analysis identified 19 well-defined obesity-relevant biological pathways from the KEGG database. MassArray® validation identified three regions located in or near miR-1203, miR-412 and miR-216A coding regions differentially methylated between obese and non-obese children. CONCLUSIONS: The current work identified three CpG sites located in coding regions of three miRNAs (miR-1203, miR-412 and miR-216A) that were differentially methylated between obese and non-obese children, suggesting a role
Autores: Etxeberria, Usune; Hijona, E.; Aguirre, L.; et al.
Revista: MOLECULAR NUTRITION AND FOOD RESEARCH
ISSN 1613-4125  Vol. 61  Nº 1  2017 
SCOPE: Nutritional interventions based on the use of natural bioactive compounds might offer new possibilities for reshaping obesity-associated bacterial dysregulation or dysbiosis and improving health. We evaluated whether pterostilbene supplementation could induce changes in gut microbiota composition and whether these modifications were associated with improvements in metabolic variables. METHODS AND RESULTS: Zucker (fa/fa) rats were given a standard diet supplemented (n = 10) or not (n = 9) with pterostilbene (15 mg/kg body weight/day) by oral gavage for 6 weeks. Faucal samples at the beginning and at the end of the intervention period were analyzed by Illumina Mi-Seq sequencing approach. Pterostilbene exerted protective antiobesity effects, improved metabolic function (insulin sensitivity), and induced structural changes in gut microbiota composition. A decrease in the levels of Firmicutes and an increase in Verrucomicrobia phyla were detected in the pterostilbene-treated group. Bacterial species belonging to genera Akkermansia and Odoribacter were also increased. A strong inverse correlation between Akkermansia muciniphila and body weight was evidenced. Odoribacter splanchnicus showed a negative correlation with adiposity. CONCLUSION: Pterostilbene modifies intestinal bacteria composition toward a healthier microbial profile and suggests that the antiobesity effects induced in Zucker rats could be associated with an enrichment of the mucin-degrading bacterial members, namely Akkermansia and Odoribacter genus.
Autores: Arpón, A.; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 73  Nº 3  2017  págs. 445 - 455
Epigenetic processes, including DNA methylation, might be modulated by environmental factors such as the diet, which in turn have been associated with the onset of several diseases such as obesity or cardiovascular events. Meanwhile, Mediterranean diet (MedDiet) has demonstrated favourable effects on cardiovascular risk, blood pressure, inflammation and other complications related to excessive adiposity. Some of these effects could be mediated by epigenetic modifications. Therefore, the objective of this study was to investigate whether the adherence to MedDiet is associated with changes in the methylation status from peripheral blood cells. A subset of 36 individuals was selected within the Prevencion con Dieta Mediterranea (PREDIMED)-Navarra study, a randomised, controlled, parallel trial with three groups of intervention in high cardiovascular risk volunteers, two with a MedDiet and one low-fat control group. Changes in methylation between baseline and 5 years were studied. DNA methylation arrays were analysed by several robust statistical tests and functional classifications. Eight genes related to inflammation and immunocompetence (EEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2, PPARGC1B) were finally selected as changes in their methylation levels correlated with adherence to MedDiet and because they presented sensitivity related to a high variability in methylation changes. Additionally, EEF2 methylation levels positively correlated with concentrations of TNF-alph
Autores: Huerta, Ana Elsa; Riezu-Boj, José Ignacio; Milagro FI; et al.
Revista: JOURNAL OF FUNCTIONAL FOODS
ISSN 1756-4646  Vol. 36  2017  págs. 178 - 185
This study aims to assess methylation modifications in blood cell genes induced by eicosapentaenoic acid (EPA) and/or ¿-lipoic acid (LA) supplementation, and their potential relationship with metabolic risk biomarkers. Healthy overweight/obese women were assigned to 4 experimental groups (control or groups supplemented with 1.3 g EPA/day, 0.3 g LA/day, or both), all followed a 10-week hypocaloric diet. White blood cells DNA was hybridized in Human-450K-methylation microarray. Differentially methylated CpGs (post¿pre) were identified in supplemented groups, including CpG regions from NCK2, FITM2, TRRAP, RPTOR and CREBBP genes. In peripheral blood mononuclear cells (PBMC), LA upregulated NCK2, TRRAP and RPTOR mRNA, which negatively associated with changes in body weight and fat mass. Changes in cg10320884 (TRRAP) methylation site negatively correlated with changes in TRRAP mRNA in PBMC, and positively with Framingham score. Further studies are needed to better characterize the potential involvement of epigenetics in the actions of LA and EPA.
Autores: Goñi, Leticia; Cuervo, M; Milagro FI; et al.
Revista: EUROPEAN JOURNAL OF NUTRITION
ISSN 1436-6207  Vol. 56  Nº 4  2017  págs. 1589 - 1596
Purpose: There is controversy about the effect of the rs1799983 nitric oxide synthase (NOS3) genetic variant on hypertension and blood pressure (BP) levels. The aims of the current study were to examine whether rs1799983 affects BP levels and to identify potential interactions between this polymorphism and other non-genetic risk factors. Methods: A total of 705 subjects were examined for anthropometric and body composition measurements, BP, dietary habits and physical activity. Oral epithelial cells were collected for the identification of rs1799983 using Luminex® 100/200TM System. Results: After adjusted for covariates, TT genotype showed a 2.30-fold higher predisposition of hypertension than GG genotype subjects. According to BP levels, for each risk allele diastolic blood pressure (DBP) increased in 1.99 mmHg. Significant interactions between rs1799983 and saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) were found. Moreover, an interaction with body weight status was observed. Among overweight individuals, T allele carriers showed higher DBP than GG genotype. Conclusion: The present study evidenced that rs1799983 NOS3 polymorphism could be associated with hypertension and DBP among Southern Europeans, being this association influenced by dietary fat (SFA and MUFA) and body mass index.
Autores: Etxeberria, Usune; Milagro FI; González-Navarro, CJ; et al.
Revista: ANALES DE LA REAL ACADEMIA NACIONAL DE FARMACIA
ISSN 1697-4271  Vol. 82  2016  págs. 234 - 259
La contribución de la microbiota intestinal al desarrollo de diversas enfermedades, incluyendo la obesidad, se está estudiando minuciosamente. Aunque los mecanismos no están completamente definidos, las perturbaciones en la composición de la microbiota intestinal parecen estar relacionados con el sobrepeso, revelando alteraciones en los niveles de Bacteriodetes y Firmicutes en comparación con individuos delgados. La modulación de la comunidad bacteriana intestinal orientada a favorecer el crecimiento de bacterias "saludables" y reducir las dañinas podría ser una eficaz herramienta terapéutica contra la obesidad. El consumo de dietas con alto contenido en grasa y azúcares afecta notablemente a la composición de la microbiota, alterando su equilibrio hacia patrones asociados a obesidad, siendo un punto de partida para un tratamiento de precisión de esta enfermedad. La interacción entre componentes de la dieta y la microbiota intestinal podría ser, en parte, responsable de sus beneficios para la salud, por lo que la administración de compuestos bioactivos podría promover el crecimiento de bacterias beneficiosas en detrimento de otras patógenas o asociadas a la obesidad. El impacto sobre el metaboloma de las intervenciones dietéticas y la administración de polifenoles se podría identificar mediante metabolómica no dirigida de las heces, permitiendo estratificar los individuos en función de la intervención dietética con el fin de aplicar tratamientos personalizados. Esta revisión pretende proporcionar una instantánea de este sistema complejo que comprende microbiota intestinal, dieta, polifenoles, metabolismo del individuo y obesidad, y cuyo conocimiento se beneficia de tecnologías avanzadas como la secuenciación de última generación y la metabolómica no dirigida.
Autores: Goñi, Leticia; Cuervo, M; Milagro FI; et al.
Revista: JOURNAL OF NUTRITION
ISSN 0022-3166  Vol. 146  Nº 4  2016  págs. 905S - 912S
As obesity has become a major global public health challenge, a large number of studies have analyzed different strategies aimed at inducing a negative energy balance and, consequently, body weight loss. However, most existing weight loss programs are generally unsuccessful, so several interventions have been carried out to identify physiologic and behavioral factors concerning this variability in order to implement more personalized treatment. Nowadays, an individualized approach is being proposed through so-called personalized nutrition, whereby not only the phenotype but also the genotype is used for customized nutrition treatment. Regarding body weight regulation, ~70 polymorphisms have been identified in or near genes related to energy expenditure, appetite, adipogenesis, insulin resistance, and lipid metabolism. Although personalized nutrition refers mainly to genetic makeup, recent advances in the investigation of the epigenome and themicrobiome open the door to implementmore personalized recommendations for bodyweightmanagement. In this context, recent studies have demonstrated the existence of several epigeneticmarkers thatmay modify gene expression and could be involved in the outcome of weight loss interventions. Moreover, different studies have shown that dietary interventions could affect the composition of gut microbiota and have an impact on body weight. The integration of nutrigenetic, epigenetic, and metagenomic data may lead to the design of more personalized dietary treatments to prevent chronic diseases and to optimize the individual's response to dietary interventions.
Autores: Gracia, A.; Miranda, J.; Fernández-Quintela, A.; et al.
Revista: FOOD & FUNCTION
ISSN 2042-6496  Vol. 7  Nº 3  2016  págs. 1680 - 1688
The epigenetic mechanisms of action of resveratrol as an anti-obesity molecule have not been fully addressed so far. The aim of the present study was to assess changes produced by resveratrol in the microRNA (miRNA) profile in white adipose tissue (WAT) and to relate these changes to those induced in the expression of genes involved in triacylglycerol metabolism. Male Wistar rats were fed (6 weeks) an obesogenic diet: a control group and a group treated with resveratrol (30 mg kg(-1) d(-1)). A miRNA microarray was carried out in perirenal adipose tissue. The overexpression of miR-539-5p and miR-1224-5p was performed in 3T3-L1 cells. Protein expression was analysed by western-blot and gene expression by qRT-PCR. Associations between variables were assessed by Pearson's correlations. The microarray showed that 3 miRNAs were decreased and 13 were increased after resveratrol treatment. Among those miRNAs increased, miR-129, miR-328-5p and miR-539-5p showed predicted target genes relevant for triacylglycerol metabolism in WAT (ppar¿: peroxisome proliferator-activated receptor gamma, hsl: hormone sensitive lipase and sp1: SP1 transcription factor) in the miRWalk database. Moreover, the literature shows that miR-1224, another miRNA up-regulated by resveratrol, can also regulate sp1. Among the three targets, only SP1 showed a reduction in protein expression. Correlation and overexpression studies revealed that the decrease in SP1 protein expression was only associated with the increase of miR-539-5p. In addition, significant reductions in SREBP1 protein expression and fasn gene expression were found in resveratrol-treated rats. In conclusion, the up-regulation of miR-539-5p is involved in the inhibition of de novo lipogenesis induced by resveratrol in WAT.
Autores: García-Lacarte, M.; Milagro FI; Zulet, María de los Ángeles; et al.
Revista: REDOX REPORT
ISSN 1351-0002  Vol. 21  Nº 2  2016  págs. 67 - 74
OBJECTIVES: Epigenetic markers, and in particular DNA methylation, have come to the fore as new tools in the personalization of the treatment of obesity and its comorbidities. The objectives of the current investigation were to identify epigenetic biomarkers that might be predictive of response to a weight-loss intervention, and to better understand the influence of certain nutrients (particularly antioxidants) on the epigenome. METHODS: Global DNA (LINE-1) methylation levels were assessed in peripheral blood mononuclear cells (PBMCs) from 96 obese volunteers of the Metabolic Syndrome Reduction in Navarra study, using a methylation-sensitive high resolution melting approach after bisulfite modification. RESULTS: Baseline LINE-1 DNA methylation levels were significantly higher (5.41%) in high responders (>8% of weight loss) as compared to low responders (<8%) to the energy-restricted treatment. Indeed, a LINE-1 methylation higher than 84.15% may be predictive of a high response to the hypocaloric diet. Statistically significant correlations were found between LINE-1 baseline DNA methylation levels and the response to the treatment involving total fat mass and body weight. Furthermore, LINE-1 baseline methylation levels positively correlated with baseline dietary total antioxidant capacity (TAC). DISCUSSION: LINE-1 methylation levels in PBMCs might be used to predict response to a dietary weight-loss intervention, and seem to be related to the dietary TAC.
Autores: Solas, Maite; Milagro FI; Martínez, Diego; et al.
Revista: TRENDS IN PHARMACOLOGICAL SCIENCES
ISSN 0165-6147  Vol. 37  Nº 7  2016  págs. 575-593
Five pharmaceutical strategies are currently approved by the US FDA for the treatment of obesity: orlistat, lorcaserin, liraglutide, phentermine/topiramate, and bupropion/naltrexone. The most effective treatment seems to be the combined administration of phentermine/topiramate followed by lorcaserin and bupropion/naltrexone. In relation to the management of excessive weight, other aspects also need to be considered, including comorbidities accompanying obesity, drug interactions, and the risk of negative collateral effects, as well as individualized treatments based on the genetic make-up. This review aims to provide an overview of the approved anti-obesity drugs and newer molecules that could affect different targets in the central nervous system or peripheral tissues, the molecular mechanisms, emerging dietary treatments and phytogenic compounds, and pharmacogenetic/nutrigenetic approaches for personalized obesity management.
Autores: Ferguson, L. R.; De-Caterina, R.; Görman, U.; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 9  Nº 1  2016  págs. 12 - 27
Diversity in the genetic profile between individuals and specific ethnic groups affects nutrient requirements, metabolism and response to nutritional and dietary interventions. Indeed, individuals respond differently to lifestyle interventions (diet, physical activity, smoking, etc.). The sequencing of the human genome and subsequent increased knowledge regarding human genetic variation is contributing to the emergence of personalized nutrition. These advances in genetic science are raising numerous questions regarding the mode that precision nutrition can contribute solutions to emerging problems in public health, by reducing the risk and prevalence of nutrition-related diseases. Current views on personalized nutrition encompass omics technologies (nutrigenomics, transcriptomics, epigenomics, foodomics, metabolomics, metagenomics, etc.), functional food development and challenges related to legal and ethical aspects, application in clinical practice, and population scope, in terms of guidelines and epidemiological factors. In this context, precision nutrition can be considered as occurring at three levels: (1) conventional nutrition based on general guidelines for population groups by age, gender and social determinants; (2) individualized nutrition that adds phenotypic information about the person's current nutritional status (e.g. anthropometry, biochemical and metabolic analysis, physical activity, among others), and (3) genotype-directed nutrition based on rare or common gene variation. Research and appropriate translation into medical practice and dietary recommendations must be based on a solid foundation of knowledge derived from studies on nutrigenetics and nutrigenomics. A scientific society, such as the International Society of Nutrigenetics/Nutrigenomics (ISNN), internationally devoted to the study of nutrigenetics/nutrigenomics, can indeed serve the commendable roles of (1) promoting science and favoring scientific communication and (2) permanently working as a 'clearing house' to prevent disqualifying logical jumps, correct or stop unwarranted claims, and prevent the creation of unwarranted expectations in patients and in the general public. In this statement, we are focusing on the scientific aspects of disciplines covering nutrigenetics and nutrigenomics issues. Genetic screening and the ethical, legal, social and economic aspects will be dealt with in subsequent statements of the Society.
Autores: Varela-Guruceaga M; Martínez, JA; et al.
Revista: ADIPOCYTE
ISSN 2162-3945  Vol. 5  Nº 1  2016  págs. 65 - 80
Adipocytes exposed to high glucose concentrations exhibit impaired metabolic function, including an increase of oxidative and proinflammatory factors that might favor the development of insulin resistance. Caveolin-1 (Cav-1) is a key mediator of the insulin transduction pathway whose expression is significantly enhanced during adipocyte differentiation. In this work, we studied the effects of high glucose concentration on the regulation of Cav-1 expression and activation and its relation to the insulin signaling pathway during the adipogenic process and in long-term differentiated adipocytes. Both, long-term high glucose exposure during adipogenesis and short-term glucose incubation of mature adipocytes, promoted triglyceride accumulation in 3T3-L1 cells. The short-term exposure of mature adipocytes to high glucose significantly reduced the sensitivity to insulin of Cav-1, insulin receptor (IR) and potein kinase B (AKT-2) phosphorylation, as well as insulin-induced deoxyglucose uptake. Adipocytes differentiated in the presence of high glucose lost Cav-1 and IR response to insulin-stimulated phosphorylation, but maintained the insulin sensitivity of AKT-2 phosphorylation and deoxyglucose uptake. Although long-term high glucose exposure increased DNA methylation in Cav-1 promoter, Cav-1 expression was not affected. Moreover, these cells showed an increase of Cav-1, IR and AKT-2 protein content, pointing to an adaptive response induced by the long-term high glucose exposure.
Autores: Carraro, J. C.; Hermsdorff, H. H.; Mansego, Maria L; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 9  Nº 2 - 4  2016  págs. 95 - 105
BACKGROUND/AIM: This study hypothesized an association between healthy dietary patterns, hypermethylation of the tumor necrosis factor-¿ (TNF-¿) promoter and decreased risk of metabolic changes. METHODS: Forty normal-weight young women were involved in this cross-sectional study. DNA was isolated from white blood cells, and CpG site methylation in TNF-¿ was analyzed by Sequenom EpiTyper. The quality of the diet was assessed by Healthy Eating Index (HEI-2005). RESULTS: Contradicting our hypothesis, HEI-2005 score was negatively associated with CpG5 (r = -0.460, p = 0.003) and TNF-¿ total methylation (r = -0.355, p = 0.026). A higher intake of fruits was related to lower insulin, HOMA-IR, and TNF-¿ methylation. No other dietary pattern was related to TNF-¿ methylation. TNF-¿ total methylation correlated positively with systolic blood pressure (r = 0.323; p = 0.042) and CpG5 methylation with body mass index (r = 0.333, p = 0.036). Furthermore, fiber intake was negatively associated with the CpG5 (r = -0.324, p = 0.041) and TNF-¿ total methylation (r = -0.434, p = 0.005), whereas vitamin C intake was negatively associated with TNF-¿ total methylation (r = -0.411, p = 0.009). Intakes of apples and citrus fruits were negatively associated with TNF-¿ total methylation. CONCLUSION: A healthy dietary pattern and higher fruit intake (particularly apples and citrus fruits) were related to better glucose tolerance in healthy subjects, which could be mediated by lower TNF-¿ methylation.
Autores: Martisová, Eva; Campión, Francisco Javier; et al.
Revista: BEHAVIOURAL BRAIN RESEARCH
ISSN 0166-4328  Vol. 299  2016  págs. 51 - 58
Adverse early life events are associated with altered stress responsiveness and metabolic disturbances in the adult life. Dietary methyl donor supplementation could be able to reverse the negative effects of maternal separation by affecting DNA methylation in the brain. In this study, maternal separation during lactation reduced body weight gain in the female adult offspring without affecting food intake, and altered total and HDL-cholesterol levels. Also, maternal separation induced a cognitive deficit as measured by NORT and an increase in the immobility time in the Porsolt forced swimming test, consistent with increased depression-like behaviour. An 18-week dietary supplementation with methyl donors (choline, betaine, folate and vitamin B12) from postnatal day 60 also reduced body weight without affecting food intake. Some of the deleterious effects induced by maternal separation, such as the abnormal levels of total and HDL-cholesterol, but especially the depression-like behaviour as measured by the Porsolt test, were reversed by methyl donor supplementation. Also, the administration of methyl donors increased total DNA methylation (measured by immunohistochemistry) and affected the expression of insulin receptor in the hippocampus of the adult offspring. However, no changes were observed in the DNA methylation status of insulin receptor and corticotropin-releasing hormone (CRH) promoter regions in the hypothalamus. In summary, methyl donor supplementation reversed some of the deleterious effects of an early life-induced model of depression in rats and altered the DNA methylation profile in the brain.
Autores: Milagro FI; Gómez-Abellán, P.; et al.
Revista: JOURNAL OF BIOLOGICAL RHYTHMS
ISSN 0748-7304  Vol. 31  Nº 3  2016  págs. 308 - 317
The circadian clock system has been linked to the onset and development of obesity and some accompanying comorbidities. Epigenetic mechanisms, such as DNA methylation, are putatively involved in the regulation of the circadian clock system. The aim of this study was to investigate the influence of a weight loss intervention based on an energy-controlled Mediterranean dietary pattern in the methylation levels of 3 clock genes, BMAL1, CLOCK, and NR1D1, and the association between the methylation levels and changes induced in the serum lipid profile with the weight loss treatment. The study sample enrolled 61 women (body mass index = 28.6 ± 3.4 kg/m(2); age: 42.2 ± 11.4 years), who followed a nutritional program based on a Mediterranean dietary pattern. DNA was isolated from whole blood obtained at the beginning and end point. Methylation levels at different CpG sites of BMAL1, CLOCK, and NR1D1 were analyzed by Sequenom's MassArray. The energy-restricted intervention modified the methylation levels of different CpG sites in BMAL1 (CpGs 5, 6, 7, 9, 11, and 18) and NR1D1 (CpGs 1, 10, 17, 18, 19, and 22). Changes in cytosine methylation in the CpG 5 to 9 region of BMAL1 with the intervention positively correlated with the eveningness profile (p = 0.019). The baseline methylation of the CpG 5 to 9 region in BMAL1 positively correlated with energy (p = 0.047) and carbohydrate (p = 0.017) intake and negatively correlated with the effect of the weight loss intervention on total cholesterol (p = 0.032) and low-density lipoprotein cholesterol (p = 0.005). Similar significant and positive correlations were found between changes in methylation levels in the CpG 5 to 9 region of BMAL1 due to the intervention and changes in serum lipids (p < 0.05). This research describes apparently for the first time an association between changes in the methylation of the BMAL1 gene with the intervention and the effects of a weight loss intervention on blood lipids levels.
Autores: Navas-Carretero, Santiago; Milagro FI; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 73  Nº 3  2016  págs. 465 - 474
Epigenetics has an important role in the regulation of metabolic adaptation to environmental modifications. In this sense, the determination of epigenetic changes in non-invasive samples during the development of metabolic diseases could play an important role in the procedures in primary healthcare practice. To help translate the knowledge of epigenetics to public health practice, the present study aims to explore the parallelism of methylation levels between white blood cells and buccal samples in relation to obesity and associated disorders. Blood and buccal swap samples were collected from a subsample of the Spanish cohort of the Food4Me study. Infinium HumanMethylation450 DNA Analysis was carried out for the determination of methylation levels. Standard deviation for ß values method and concordance correlation analysis were used to select those CpG which showed best parallelism between samples. A total of 277 CpGs met the criteria and were selected for an enrichment analysis and a correlation analysis with anthropometrical and clinical parameters. From those selected CpGs, four presented high associations with BMI (cg01055691 in GAP43; r = -0.92 and rho = -0.84 for blood; r = -0.89 and rho = -0.83 for buccal sample), HOMA-IR (cg00095677 in ATP2A3; r = 0.82 and rho = -0.84 for blood; r = -0.8 and rho = -0.83 for buccal sample) and leptin (cg14464133 in ADARB2; r = -0.9182 and rho = -0.94 for blood; r = -0.893 and rho = -0.79 for buccal sample). These findings demonstrate the potential application of non-invasive buccal samples in the identification of surrogate epigenetic biomarkers and identify methylation sites in GAP43, ATP2A3 and ADARB2 genes as potential targets in relation to overweight management and insulin sensibility.
Autores: Goñi, Leticia; Cuervo, M; Milagro FI; et al.
Revista: JOURNAL OF NUTRITION
ISSN 0022-3166  Vol. 146  Nº 4  2016  págs. 905S - 912S
As obesity has become a major global public health challenge, a large number of studies have analyzed different strategies aimed at inducing a negative energy balance and, consequently, body weight loss. However, most existing weight loss programs are generally unsuccessful, so several interventions have been carried out to identify physiologic and behavioral factors concerning this variability in order to implement more personalized treatment. Nowadays, an individualized approach is being proposed through so-called personalized nutrition, whereby not only the phenotype but also the genotype is used for customized nutrition treatment. Regarding body weight regulation, similar to 70 polymorphisms have been identified in or near genes related to energy expenditure, appetite, adipogenesis, insulin resistance, and lipid metabolism. Although personalized nutrition refers mainly to genetic makeup, recent advances in the investigation of the epigenome and themicrobiome open the door to implement more personalized recommendations for body weight management. In this context, recent studies have demonstrated the existence of several epigenetic markers that may modify gene expression and could be involved in the outcome of weight loss interventions. Moreover, different studies have shown that dietary interventions could affect the composition of gut microbiota and have an impact on body weight. The integration of nutrigenetic, epigenetic, and metagenomic data may lead to the design of more personalized dietary treatments to prevent chronic diseases and to optimize the individual's response to dietary interventions.
Autores: Marques-Rocha, J. L.; Milagro FI; Mansego, Maria L; et al.
Revista: EPIGENETICS
ISSN 1559-2294  Vol. 11  Nº 1  2016  págs. 49 - 60
With the goal of investigating if epigenetic biomarkers from white blood cells (WBC) are associated with dietary, anthropometric, metabolic, inflammatory and oxidative stress parameters in young and apparently healthy individuals. We evaluated 156 individuals (91 women, 65 men; age: 23.1±3.5 years; body mass index: 22.0±2.9 kg/m(2)) for anthropometric, biochemical and clinical markers, including some components of the antioxidant defense system and inflammatory response. DNA methylation of LINE-1, TNF-¿ and IL-6 and the expression of some genes related to the inflammatory process were analyzed in WBC. Adiposity was lower among individuals with higher LINE-1 methylation. On the contrary, body fat-free mass was higher among those with higher LINE-1 methylation. Individuals with higher LINE-1 methylation had higher daily intakes of calories, iron and riboflavin. However, those individuals who presented lower percentages of LINE-1 methylation reported higher intakes of copper, niacin and thiamin. Interestingly, the group with higher LINE-1 methylation had a lower percentage of current smokers and more individuals practicing sports. On the other hand, TNF-¿ methylation percentage was negatively associated with waist girth, waist-to-hip ratio and waist-to-stature ratio. Plasma TNF-¿ levels were lower in those individuals with higher TNF-¿ methylation. This study suggests that higher levels of LINE-1 and TNF-¿ methylation are associated with better indicators of adiposity status in healthy young individuals. In addition, energy and micronutrient intake, as well as a healthy lifestyle, may have a role in the regulation of DNA methylation in WBC and the subsequent metabolic changes may affect epigenetic biomarkers.
Autores: Marques-Rocha, J. L.; Milagro FI; Mansego, Maria L; et al.
Revista: NUTRITION
ISSN 0550-404X  Vol. 32  Nº 1  2016  págs. 48 - 55
Objectives The aim of this study was to evaluate the influence of a dietary strategy for weight loss (the RESMENA [reduction of metabolic syndrome in Navarra, Spain] diet) on the expression of inflammation-related microRNAS (miRNAs) and genes in white blood cells (WBC) from individuals with metabolic syndrome (MetS). Methods The clinical, anthropometric, and biochemical characteristics of 40 individuals with MetS (20 men and 20 women; age: 48.84 ± 10.02 y; body mass index: 35.41 ± 4.42 kg/m2) were evaluated before and after an 8-wk hypocaloric diet based on the Mediterranean dietary pattern. Nutrient intake was assessed with a food frequency questionnaire and 48-h weighed food records. Total RNA was isolated from WBC and the expression of some inflammation-related miRNAs and mRNAs (IL-6, TNF-¿, ICAM-1, IL-18, SERPINE1, VCAM-1, GAPDH) was assessed by quantitative polymerase chain reaction. Results The RESMENA nutritional intervention improved most anthropometric and biochemical features. The expression of miR-155-3p was decreased in WBC, whereas Let-7b was strongly upregulated as a consequence of the dietary treatment. However, they were not correlated with the expression of the proinflammatory genes in the same cells. The changes in the expression of let-7b, miR-125b, miR-130a, miR-132-3p, and miR-422b were significantly associated with changes in diet quality when assessed by the Healthy Eating Index. Moreover, low consumption of lipids and saturated fat (g/d) were associated with higher expression of let-7b after the nutritional intervention. Conclusions The Mediterranean-based nutritional intervention was able to induce changes in the expression of let-7b and miR-155-3p in WBC from patients with MetS after 8 wk. Moreover, the quality of the diet has an important effect on the miRNAs expression changes. These results should be highlighted because these miRNAs have been associated with inflammatory gene regulation and important human diseases.
Autores: Carraro, J. C.; Mansego, Maria L; Milagro FI; et al.
Revista: BIOMARKERS
ISSN 1354-750X  Vol. 21  Nº 7  2016  págs. 625 - 632
We analyzed whether global and inflammatory genes methylation can be early predictors of metabolic changes and their associations with the diet, in a cross-sectional study (n = 40). Higher global methylation was associated to adiposity, insulin resistance, and lower quality of the diet. Methylation of IL-6, SERPINE1 and CRP genes was related to adiposity traits and macronutrients intake. SERPINE1 hypermethylation was also related to some metabolic alterations. CRP methylation was a better predictor of insulin resistance than CRP plasma concentrations. Global and inflammatory gene promoter hypermethylation can be good early biomarkers of adiposity and metabolic changes and are associated to the quality of the diet.
Autores: Nicoletti, C. F.; Nonino, C. B.; de Oliveira, B. A.; et al.
Revista: OBESITY SURGERY
ISSN 0960-8923  Vol. 26  Nº 3  2016  págs. 603 - 611
Weight loss can be influenced by genetic factors and epigenetic mechanisms that participate in the regulation of body weight. This study aimed to investigate whether the weight loss induced by two different obesity treatments (energy restriction or bariatric surgery) may affect global DNA methylation (LINE-1) and hydroxymethylation profile, as well as the methylation patterns in inflammatory genes. This study encompassed women from three differents groups: 1. control group (n = 9), normal weight individuals; 2. energy restriction group (n = 22), obese patients following an energy-restricted Mediterranean-based dietary treatment (RESMENA); and 3. bariatric surgery group (n = 14), obese patients underwent a hypocaloric diet followed by bariatric surgery. Anthropometric measurements and 12-h fasting blood samples were collected before the interventions and after 6 months. Lipid and glucose biomarkers, global hydroxymethylation (by ELISA), LINE-1, SERPINE-1, and IL-6 (by MS-HRM) methylation levels were assessed in all participants. Baseline LINE-1 methylation was associated with serum glucose levels whereas baseline hydroxymethylation was associated with BMI, waist circumference, total cholesterol, and triglycerides. LINE-1 and SERPINE-1 methylation levels did not change after weight loss, whereas IL-6 methylation increased after energy restriction and decreased in the bariatric surgery group. An association between SERPINE-1 methylation and weight loss responses was found. Global DNA methylation and hydroxymethylation might be biomarkers for obesity and associated comorbidities. Depending on the obesity treatment (diet or surgery), the DNA methylation patterns behave differently. Baseline SERPINE-1 methylation may be a predictor of weight loss values after bariatric surgery.
Autores: Milagro FI; Moreno-Aliaga MJ; Martínez, JA;
Revista: NEW ENGLAND JOURNAL OF MEDICINE
ISSN 0028-4793  Vol. 374  Nº 2  2016  págs. 190 - 191
Autores: Remely, M.; Lovrecic, L.; de la Garza, Ana Laura Isabel; et al.
Revista: BRITISH JOURNAL OF PHARMACOLOGY
ISSN 0007-1188  Vol. 172  Nº 11  2015  págs. 2756 - 2768
Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction.
Autores: Martínez, JA; Milagro FI;
Revista: TRENDS IN FOOD SCIENCE AND TECHNOLOGY
ISSN 0924-2244  Vol. 42  Nº 2  2015  págs. 97 - 115
A personalized nutritional approach, based not only on phenotypic traits but also on genetic make-up, may help to control body weight and obesity. Recent advances in nutrigenetics, bioinformatics and genome-wide association/metabolomic/metagenomic studies are set to unleash a revolution in personalized nutrition. This article performs a systematic review of nutrigenetic data concerning single nucleotide polymorphisms (SNPs) involved in weight loss that are considered polygenic. SNPs located in or near FTO, MC4R, MC3R, POMC, LEP, LEPR, PLIN1, APOA5, LIPC, FABP2, INSIG2, IRS1, GIPR, ADBR2, ADRB3, UCP1, RETN, ADIPOQ, IL6, PPARG, TCF7L2, and CLOCK, among others, are comprehensively reviewed.
Autores: Marques-Rocha, J. L.; Milagro FI; et al.
Revista: FASEB JOURNAL
ISSN 0892-6638  Vol. 29  Nº 9  2015  págs. 3595 - 3611
Chronic inflammation is involved in the onset and development of many diseases, including obesity, atherosclerosis, type 2 diabetes, osteoarthritis, autoimmune and degenerative diseases, asthma, periodontitis, and cirrhosis. The inflammation process is mediated by chemokines, cytokines, and different inflammatory cells. Although the molecules and mechanisms that regulate this primary defense mechanism are not fully understood, recent findings offer a putative role of noncoding RNAs, especially microRNAs (miRNAs), in the progression and management of the inflammatory response. These noncoding RNAs are crucial for the stability and maintenance of gene expression patterns that characterize some cell types, tissues, and biologic responses. Several miRNAs, such as miR-126, miR-132, miR-146, miR-155, and miR-221, have emerged as important transcriptional regulators of some inflammation-related mediators. Additionally, little is known about the involvement of long noncoding RNAs, long intergenic noncoding RNAs, and circular RNAs in inflammation-mediated processes and the homeostatic imbalance associated with metabolic disorders. These noncoding RNAs are emerging as biomarkers with diagnosis value, in prognosis protocols, or in the personalized treatment of inflammation-related alterations. In this context, this review summarizes findings in the field, highlighting those noncoding RNAs that regulate inflammation, with emphasis on recognized mediators such as TNF-alpha, IL-1, IL-6, IL-18, intercellular adhesion molecule 1, VCAM-1, and plasminogen activator inhibitor 1. The down-regulation or antagonism of the noncoding RNAs and the administration of exogenous miRNAs could be, in the near future, a promising therapeutic strategy in the treatment of inflammation-related diseases.
Autores: Martínez, JA; Milagro FI;
Título: Beyond the genome
Revista: NATURE
ISSN 0028-0836  Vol. 518  Nº 7539  2015  págs. 273
Studies of the epigenomic signatures of many healthy and diseased human tissues could provide crucial information to link genetic variation and disease.
Autores: González-Muniesa, P; et al.
Revista: BRITISH JOURNAL OF NUTRITION
ISSN 0007-1145  Vol. 113  Nº 2  2015  págs. 331 - 342
The present study analyses the gene expression profile of peripheral blood mononuclear cells (PBMC) from obese boys. The aims of the present study were to identify baseline differences between low responders (LR) and high responders (HR) after 10 weeks of a moderate energy-restricted dietary intervention, and to compare the gene expression profile between the baseline and the endpoint of the nutritional intervention. Spanish obese boys (age 10-14 years) were advised to follow a 10-week moderate energy-restricted diet. Participants were classified into two groups based on the association between the response to the nutritional intervention and the changes in BMI standard deviation score (BMI-SDS): HR group (n 6), who had a more decreased BMI-SDS; LR group (n 6), who either maintained or had an even increased BMI-SDS. The expression of 28 869 genes was analysed in PBMC from both groups at baseline and after the nutritional intervention, using the Affymetrix Human Gene 1.1 ST 24-Array plate microarray. At baseline, the HR group showed a lower expression of inflammation and immune response-related pathways, which suggests that the LR group could have a more developed pro-inflammatory phenotype. Concomitantly, LEPR and SIRPB1 genes were highly expressed in the LR group, indicating a tendency towards an impaired immune response and leptin resistance. Moreover, the moderate energy-restricted diet was able to down-regulate the inflammatory 'mitogen-activated protein kinase signalling pathway' in the HR group, as well as some inflammatory genes (AREG and TNFAIP3). The present study confirms that changes in the gene expression profile of PBMC in obese boys may help to understand the weight-loss response. However, further research is required to confirm these findings.
Autores: Etxeberria, Usune; Castilla, Rosa María; Lostao MP; et al.
Revista: CELLULAR AND MOLECULAR BIOLOGY
ISSN 0145-5680  Vol. 61  Nº 8  2015  págs. 9 - 16
A DNA microarray analysis was conducted in Caco-2 cells to analyse the protective effects of trans-resveratrol on enterocyte physiology and metabolism in pro-inflammatory conditions. Cells were pre-treated with 50 ¿¿ of trans-resveratrol and, subsequently, lipopolysaccharide (LPS) was added for 48 h. The microarray analysis revealed 121 genes differentially expressed between resveratrol-treated and non-treated cells (B> 0, is the odd thatthe gene is differentially expressed). Inhibitor of DNA binding 1 (ID1), histidine-rich glycoprotein (HRG), NADPH oxidase (NOX1) and sprouty homolog 1 (SPRY), were upregulated by LPS treatment, but significantly blocked by trans-resveratrol pre-treatment (padj< 0.05, after adjusting for Benjamini-Hocheberg procedure). Moreover, genes implicated in synthesis of lipids (z-score= -1.195) and concentration of cholesterol (z-score= -0.109), were markedly downregulated by trans-resveratrol. Other genes involved in fat turnover, but also in cell death and survival function, such as transcription factors Krüppel-like factor 5 (KLF5) and amphiregulin (AREG), were also significantly inhibited by trans-resveratrol pre-treatment. RT-qPCR-data confirmed the microarray results. Special mention deserves acyl-CoA synthetase long-chain family member 3 (ACSL3) and endothelial lipase (LIPG), which were downregulated by this stilbene and have been previously associated with fatty acid synthesis and obesity in other tissues. This study envisages that trans-resveratrol might exert an important anti-lipogenic effect at intestinal level under pro-inflammatory conditions, which has not been previously described.
Autores: Mansego, Maria L; Milagro FI; Zulet, María de los Ángeles; et al.
Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067  Vol. 16  Nº 8  2015  págs. 16816 - 16832
The aim of this study was to evaluate whether genome-wide levels of DNA methylation are associated with age and the health risks of obesity (HRO); defined according to BMI categories as "Low HRO" (overweight and class 1 obesity) versus "High HRO" (class 2 and class 3 obesity). Anthropometric measurements were assessed in a subsample of 48 volunteers from the Metabolic Syndrome Reduction in Navarra (RESMENA) study and 24 women from another independent study, Effects of Lipoic Acid and Eicosapentaenoic Acid in Human Obesity (OBEPALIP study). In the pooled population; the methylation levels of 55 CpG sites were significantly associated with age after Benjamini-Hochberg correction. In addition, DNA methylation of three CpG sites located in ELOVL2; HOXC4 and PI4KB were further negatively associated with their mRNA levels. Although no differentially methylated CpG sites were identified in relation to HRO after multiple testing correction; several nominally significant CpG sites were identified in genes related to insulin signaling; energy and lipid metabolism. Moreover, statistically significant associations between BMI or mRNA levels and two HRO-related CpG sites located in GPR133 and ITGB5 are reported. As a conclusion, these findings from two Spanish cohorts add knowledge about the important role of DNA methylation in the age-related regulation of gene expression. In addition; a relevant influence of age on DNA methylation in white blood cells was found, as well as, on a trend level, novel associations between DNA methylation and obesity.
Autores: Etxeberria, Usune; Arias, N.; Boqué, Noemi; et al.
Revista: JOURNAL OF NUTRITIONAL BIOCHEMISTRY
ISSN 0955-2863  Vol. 26  Nº 6  2015  págs. 651 - 660
Diet-induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability, and when they reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans-resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high-fat sucrose diet (HFS) and, in turn, improve gut health. Wistar rats were randomised into four groups fed an HFS diet supplemented or not with trans-resveratrol [15 mg/kg body weight (BW)/day], quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans-resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet-induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS-diet-induced gut microbiota dysbiosis. In contrast, trans-resveratrol supplementation alone or in combination with quercetin scarcely modified the profile of gut bacteria but acted at the intestinal level, altering the mRNA expression of tight-junction proteins and inflammation-associated genes.
Autores: Milagro FI; Mansego, Maria L; et al.
Revista: HUMAN MOLECULAR GENETICS
ISSN 0964-6906  Vol. 24  Nº 5  2015  págs. 1432 - 1440
Obesity and stroke are multifactorial diseases in which genetic, epigenetic and lifestyle factors are involved. The research aims were, first, the description of genes with differential epigenetic regulation obtained by an 'omics' approach in patients with ischemic stroke and, second, to determine the importance of some regions of these selected genes in biological processes depending on the body mass index. A case-control study using two populations was designed. The first population consisted of 24 volunteers according to stroke/non-stroke and normal weight/obesity conditions. The second population included 60 stroke patients and 55 controls classified by adiposity. DNA from the first population was analyzed with a methylation microarray, showing 80 cytosine-guanine dinucleotides (CpG) sites differentially methylated in stroke and 96 CpGs in obesity, whereas 59 CpGs showed interaction. After validating these data by MassArray Epityper, the promoter region of peptidase M20 domain containing 1 (PM20D1) gene was significantly hypermethylated in stroke patients. One CpG site at Caldesmon 1 (CALD1) gene showed an interaction between stroke and obesity. Two CpGs located in the genes Wilms' tumor 1 (WT1) and potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) were significantly hypermethylated in obese patients. In the second population, KCNQ1 was also hypermethylated in the obese subjects. Two CpGs of this gene were subsequently validated by methylation-sensitive high-resolution melting. Moreover, KCNQ1 methylation levels were associated with plasma KCNQ1 protein concentrations. In conclusion, obesity induced changes in the KCNQ1 methylation pattern which were also dependent on stroke. Furthermore, the epigenetic marks differentially methylated in the stroke patients were dependent on the previous obese state. These DNA methylation patterns could be used as future potential stroke biomarkers.
Autores: Mansego, Maria L; Milagro FI; Zulet, María de los Ángeles; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 66  Nº 1  2015  págs. 1 - 9
The objective of this study was to examine whether 7 SNPs previously associated with obesity-related traits that add or remove potential sites of DNA methylation are accompanied by differential DNA methylation and subsequently affect adiposity variables or body weight reduction in WBC from obese subjects under an energy-restricted program. Material and Methods: Anthropometric measurements were assessed in 47 volunteers recruited within the RESMENA study (Spain). At baseline, DNA from white blood cells was isolated and 7 obesity-related trait CpG-SNPs were genotyped by TaqMan-PCR. Then, methylation levels of CpG-SNP sites were quantified by MassArray® EpiTyper¿ or MS-HRM approaches. Results: Differential DNA methylation levels were observed by genotypes in all of the CpG-SNPs analyzed. The FTO and BDNF methylation levels were further correlated with baseline body weight and, BDNF mRNA levels and body weight change, respectively. Moreover, the rs7359397 (SH2B1) was associated with the body weight, body mass index, and truncal fat mass reduction. Conclusions: Our results reveal the interaction of epigenetic and genetic variations in CpG-SNPs, especially in BDNF and SH2B1 genes, and how allele-specific methylation may contribute to elucidate the possible molecular mechanisms as these SNPs are affecting the decrease of mRNA levels and contributing to a lower body weight reduction.
Autores: Goñi, Leticia; Cuervo, M; Milagro FI; et al.
Revista: GENES AND NUTRITION
ISSN 1555-8932  Vol. 10  Nº 1  2015  págs. 445
There is little evidence about genetic risk score (GRS)-diet interactions in order to provide personalized nutrition based on the genotype. The aim of the study was to assess the value of a GRS on obesity prediction and to further evaluate the interactions between the GRS and dietary intake on obesity. A total of 711 seekers of a Nutrigenetic Service were examined for anthropometric and body composition measurements and also for dietary habits and physical activity. Oral epithelial cells were collected for the identification of 16 SNPs (related with obesity or lipid metabolism) using DNA zip-coded beads. Genotypes were coded as 0, 1 or 2 according to the number of risk alleles, and the GRS was calculated by adding risk alleles with such a criterion. After being adjusted for gender, age, physical activity and energy intake, the GRS demonstrated that individuals carrying >7 risk alleles had in average 0.93 kg/m(2) of BMI, 1.69 % of body fat mass, 1.94 cm of waist circumference and 0.01 waist-to-height ratio more than the individuals with ¿7 risk alleles. Significant interactions for GRS and the consumption of energy, total protein, animal protein, vegetable protein, total fat, saturated fatty acids, polyunsaturated fatty acids, total carbohydrates, complex carbohydrates and fiber intake on adiposity traits were found after adjusted for confounders variables. The GRS confirmed that the high genetic risk group showed greater values of adiposity than the low risk group and demonstrated that macronutrient intake modifies the GRS association with adiposity traits.
Autores: Milagro FI; Riezu-Boj, José Ignacio; Martínez, JA;
Revista: CURRENT NUTRITION REPORTS
ISSN 2161-3311  Vol. 4  Nº 4  2015  págs. 330 - 339
Epigenetic signatures, which can sometimes be transgenerationally inherited, include DNA methylation, histone covalent modifications, or chromatin folding, as well as microRNAs and other mechanisms that can regulate gene expression without altering the underlying genomic sequence. Maternal malnutrition during perinatal periods has been involved, through fetal or developmental programming, in the susceptibility to excessive adiposity and other non-communicable chronic diseases. Epigenetic encrypts in the adipose tissue of obese subjects, which are affected by nutrition, sedentarism, and age among other factors, can be also reflected in the blood cells. Relationships between obesity and the epigenetic regulation of gene expression have been repeatedly reported, for example. It has been suggested that the obesity status may be mediated by epigenetic marks and that the response to a hypocaloric diet could be related to the methylation profiles of specific gene promoters. This review is focused on the importance of epigenetic regulation, with emphasis on DNA methylation, in the etiology and development of obesity, presenting some target epiobesogenic genes that might be used as biomarkers of weight loss success and weight regain and for preventive and personalized nutrition.
Autores: Etxeberria, Usune; Arias, N.; Boqué, Noemi; et al.
Revista: FOOD & FUNCTION
ISSN 2042-6496  Vol. 6  Nº 8  2015  págs. 2758 - 2767
Faecal non-targeted metabolomics deciphers metabolic end-products resulting from the interactions among food, host genetics, and gut microbiota. Faeces from Wistar rats fed a high-fat sucrose (HFS) diet supplemented with trans-resveratrol and quercetin (separately or combined) were analysed by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Metabolomics in faeces are categorised into four clusters based on the type of treatment. Tentative identification of significantly differing metabolites highlighted the presence of carbohydrate derivatives or conjugates (3-phenylpropyl glucosinolate and dTDP-D-mycaminose) in the quercetin group. The trans-resveratrol group was differentiated by compounds related to nucleotides (uridine monophosphate and 2,4-dioxotetrahydropyrimidine D-ribonucleotide). Marked associations between bacterial species (Clostridium genus) and the amount of some metabolites were identified. Moreover, trans-resveratrol and resveratrol-derived microbial metabolites (dihydroresveratrol and lunularin) were also identified. Accordingly, this study confirms the usefulness of omics-based techniques to discriminate individuals depending on the physiological effect of food constituents and represents an interesting tool to assess the impact of future personalized therapies.
Autores: Cordero, Paúl; González-Muniesa, P; Milagro FI; et al.
Revista: JOURNAL OF ANIMAL PHYSIOLOGY AND ANIMAL NUTRITION
ISSN 0931-2439  Vol. 99  Nº 5  2015  págs. 834 - 840
Maternal nutrition during pregnancy and lactation influences offspring development and health. Novel studies have described the effects on next generation obesity-related features depending on maternal macro- and micro-nutrient perinatal feeding. We hypothesized that the maternal obesogenic diet during pregnancy and lactation programs an obese phenotype, while maternal micronutrient supplementation at these stages could partially prevent these features. Thus, the aim was to assess the influence of a perinatal maternal feeding with an obesogenic diet enriched in fat and sucrose and a micronutrient supplementation during pregnancy and lactation on offspring growth and obese phenotypical features during life course. Female Wistar rats were assigned to four dietary groups during pregnancy and lactation: control, control supplemented with micronutrients (choline, betaine, folic acid and vitamin B12 ), high-fat sucrose (HFS) and HFS supplemented. At weaning, the offspring were transferred to a chow diet, and weight and fat mass were measured at weeks 3, 12 and 20. At birth, both male and female offspring from mothers fed the obesogenic diet showed lower body weight (-5 and -6%, respectively), while only female offspring weight decreased by maternal micronutrient supplementation (-5%). During lactation, maternal HFS diet was associated with increased body weight, while micronutrient supplementation protected against body weight gain. Whole body fat mass content increased at weeks 3, 12 and 20 (from 16 to 65%) due to maternal HFS diet. Maternal micronutrient supplementation decreased offspring fat mass content at week 3 (-8%). Male offspring showed higher adiposity than females at weeks 12 and 20. In conclusion, maternal HFS feeding during pregnancy and lactation was associated with a low offspring weight at birth and obese phenotypical features during adult life in a sex- and time-dependent manner. Furthermore, maternal methyl donor supplementation protected against body weight gain in male offspring during lactation and in female offspring also during juvenile period.
Autores: Etxeberria, Usune; de la Garza, Ana Laura Isabel; Martínez, JA; et al.
Revista: NATURAL PRODUCT COMMUNICATIONS
ISSN 1934-578X  Vol. 10  Nº 8  2015  págs. 1417 - 1420
The use of biocompounds as agents with potential anti-obesity effects might be a feasible alternative to the prescription of traditional drugs in the near future. The goal of the present study was to screen five different compounds in relation to their ability to prevent body weight gain and ameliorate obesity-associated metabolic impairments, namely insulin resistance. For this purpose, seventy Wistar rats were randomly assigned into seven experimental groups. A standard diet-fed control group (control, n=10); a high-fat, high-sucrose diet-fed group (BPS, n=10) and five experimental groups which were fed the I-IFS diet supplemented with one of the following biocompounds; curcumin (100 mg/kg bw, n=10), chlorogenic acid (50 mg/kg bw, n=10), coumaric acid (100 mg/kg bw, n=10), naringin (100 mg/kg bw, n=10) and leucine (1 % of diet, n=10). These results confirm the effectiveness of all the compounds to reduce significantly food efficiency, despite the significant higher food intake. Moreover, visceral fat mass percentage was significantly decreased after naringin and coumaric acid supplementation. In fact, this finding might be related to the considerable amelioration of HOMA-IR index detected in naringin-treated animals. A significant reduction in serum insulin levels and an improvement in the intraperitoneal glucose tolerance test and AUC were found in leucine- and coumaric acid-treated rats, respectively. In summary, the tested biocompounds, particularly naringin, coumaric acid and leucine, showed potential benefits in the prevention of obesity-related complications in rats, at least at the proved doses.
Autores: Cardoso-Carraro, J. C.; Hermsdorff, H. H.; Puchau, María Blanca; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 71  Nº 3  2015  págs. 527 - 535
Autores: de la Garza, Ana Laura Isabel; Etxeberria, Usune; Haslberger, A.; et al.
Revista: JOURNAL OF MEDICINAL FOOD
ISSN 1096-620X  Vol. 18  Nº 8  2015  págs. 890 - 898
Obesity is characterized by an increased production of inflammatory markers. High levels of circulating free fatty acids and chronic inflammation lead to increased oxidative stress, contributing to the development of insulin resistance (IR). Recent studies have focused on the potential use of flavonoids for obesity management due to their antioxidant and anti-inflammatory properties. This study was designed to investigate the antioxidant and anti-inflammatory effects of helichrysum and grapefruit extracts in overweight insulin-resistant rats. Thirty-eight male Wistar rats were randomly distributed in two groups: control group (n=8) and high-fat sucrose (HFS) group (n=30). After 22 days of ad libitum water and food access, the rats fed HFS diet changed to standard diet and were reassigned into three groups (n=10 each group): nonsupplemented, helichrysum extract (2g/kg bw), and grapefruit extract (1g/kg bw) administered for 5 weeks. Rats supplemented with both extracts gained less body weight during the 5-week period of treatment, showed lower serum insulin levels and liver TBARS levels. Leptin/adiponectin ratio, as an indicator of IR, was lower in both extract-administered groups. These results were accompanied by a reduction in TNFalpha gene expression in epididymal adipose tissue and intestinal mucosa, and TLR2 expression in intestinal mucosa. Helichrysum and grapefruit extracts might be used as complement hypocaloric diets in weight loss treatment. Both extracts helped to reduce weight gain, hyperinsulinemia, and IR, improved inflammation markers, and decreased the HFS diet-induced oxidative stress in insulin-resistant rats.
Autores: Abete, Itziar; Mansego, Maria L; et al.
Revista: CURRENT NEUROVASCULAR RESEARCH
ISSN 1567-2026  Vol. 12  Nº 4  2015  págs. 321 - 333
Ischemic stroke patients often show high concentrations of circulating inflammatory markers that are associated with increased risk of recurrence. Epigenetic mechanisms could be involved in obesity, inflammation and stroke. The objective of this research was to investigate, in obese patients suffering a previous stroke, the effects of a nutritional program on anthropometric and biochemical variables, and on the methylation patterns of two stroke-related genes (KCNQ1: potassium channel, voltage gated KQT-like subfamily Q, member 1; and WT1: Wilms tumor 1). Twenty-two ischemic stroke patients were compared with a control group composed of eighteen obese subjects with similar age and body mass index ranges. Both groups followed a 20-week nutritional program based on an energy-restricted balanced diet with high adherence to the Mediterranean dietary pattern. The intervention significantly improved anthropometric and metabolic variables, such as the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and C-reactive protein concentration, in ischemic stroke patients, and was accompanied by changes in the methylation patterns of both stroke-related genes, which correlated with anthropometric and biochemical variables.
Autores: Varela-Guruceaga M; Algarabel, M.; et al.
Revista: CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1015-8987  Vol. 36  Nº 4  2015  págs. 1499 - 1516
BACKGROUND/AIMS: Tumor necrosis factor-¿ (TNF-¿)-mediated chronic low-grade inflammation of adipose tissue is associated with obesity and insulin resistance. Caveolin-1 (Cav-1) is the central component of adipocyte caveolae and has an essential role in the regulation of insulin signaling. The effects of TNF-¿ on Cav-1 expression and insulin signaling during adipocyte differentiation and in mature adipocytes were studied. METHODS: 3T3-L1 cells were differentiated (21 days) in the presence TNF-¿ (10 ng/mL) and mature adipocytes were also treated with TNF-¿ for 48 hours. Cav-1 and insulin receptor (IR) gene methylation were determined as well as Cav-1, IR, PKB/AKT-2 and Glut-4 expression and activation by real time RT-PCR and western blot. Baseline and insulin-induced glucose uptake was measured by the 2-[C14]-deoxyglucose uptake assay. RESULTS: TNF-¿ slowed down the differentiation program, hindering the expression of some insulin signaling intermediates without fully eliminating insulin-mediated glucose uptake. In mature adipocytes, TNF-¿ did not compromise lipid-storage capacity, but downregulated the expression of the insulin signaling intermediates, totally blocking insulin-mediated glucose uptake. Insulin sensitivity correlated with the level of activated phospho-Cav-1 in both situations, strongly suggesting the direct contribution of Cav-1 to the maintenance of this physiological response. CONCLUSION: Cav-1 activation by phosphorylation seems to be essential for the maintenance of an active and insulin-sensitive glucose uptake.
Autores: Goñi, Leticia; Milagro FI; Cuervo, M; et al.
Revista: NUTRITION REVIEWS
ISSN 0029-6643  Vol. 72  Nº 11  2014  págs. 673 - 690
Visceral fat is strongly associated with the development of specific obesity-related metabolic alterations. Genetic and epigenetic mechanisms seem to be involved in the development of obesity and visceral adiposity. The aims of this review are to identify the single-nucleotide polymorphisms related to central obesity and to summarize the main findings on DNA methylation and obesity. A search of the MEDLINE database was conducted to identify genome-wide association studies, meta-analyses of genome-wide association studies, and gene-diet interaction studies related to central obesity, and, in addition, studies that analyzed DNA methylation in relation to body weight regulation. A total of 8 genome-wide association studies and 9 meta-analyses of genome-wide association studies reported numerous single-nucleotide polymorphisms to be associated with central obesity. Ten studies analyzed gene-diet interactions and central obesity, while 2 epigenome-wide association studies analyzed DNA methylation patterns and obesity. Nine studies investigated the relationship between DNA methylation and weight loss, excess body weight, or adiposity outcomes. Given the development of new sequencing and omics technologies, significantly more knowledge on genomics and epigenomics of obesity and body fat distribution will emerge in the near future.
Autores: Martínez, JA; Milagro FI; Claycombe, K. J.; et al.
Revista: ADVANCES IN NUTRITION
ISSN 2161-8313  Vol. 5  2014  págs. 71 - 81
Given the role that diet and other environmental factors play in the development of obesity and type 2 diabetes, the implication of different epigenetic processes is being investigated. Although it is well known that external factors can cause cell type-dependent epigenetic changes, including DNA methylation, histone tail modifications, and chromatin remodeling, the regulation of these processes, the magnitude of the changes and the cell types in which they occur, the individuals more predisposed, and the more crucial stages of life remain to be elucidated. There is evidence that obese and diabetic people have a pattern of epigenetic marks different from nonobese and nondiabetic individuals. The main long-term goals in this field are the identification and understanding of the role of epigenetic marks that could be used as early predictors of metabolic risk and the development of drugs or diet-related treatments able to delay these epigenetic changes and even reverse them. But weight gain and insulin resistance/diabetes are influenced not only by epigenetic factors; different epigenetic biomarkers have also been identified as early predictors of weight loss and the maintenance of body weight after weight loss. The characterization of all the factors that are able to modify the epigenetic signatures and the determination of their real importance are hindered by the following factors: the magnitude of change produced by dietary and environmental factors is small and cumulative; there are great differences among cell types; and there are many factors involved, including age, with multiple interactions between them.
Autores: Cordero, Paúl; Milagro FI; Campión, Francisco Javier; et al.
Revista: JOURNAL OF DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE
ISSN 2040-1744  Vol. 5  Nº 5  2014  págs. 385 - 395
Methyl donor supplementation has been reported to prevent obesity-induced liver fat accumulation in adult rats. We hypothesized that this protection could be mediated by perinatal nutrition. For this purpose, we assessed the response to an obesogenic diet (high-fat-sucrose, HFS) during adulthood depending on maternal diet during lactation. Female Wistar rats fed control diet during pregnancy were assigned to four postpartum dietary groups: control, control supplemented with methyl donors (choline, betaine, folic acid, vitamin B12), HFS and HFS supplemented with methyl donors. At weaning, the male offspring was transferred to a chow diet and at week 12th assigned to a control or a HFS diet during 8 weeks. The offspring whose mothers were fed HFS during lactation showed increased adiposity (19%, P<0.001). When fed the HFS diet as adults, offspring whose mothers were HFS supplemented had more body fat (23%, P<0.001) than those from HFS non-supplemented. However, they showed lower liver fat accumulation (¿18%, P<0.001). Srebf1, Dnmt1 and Lepr liver mRNA levels increased after adulthood HFS feeding. In those animals HFS fed during adulthood, previous maternal HFS decreased Lepr and Dnmt1 expression levels when compared with c-HFS offspring, while the supplementation of control and HFS-fed dams, respectively, induced higher hepatic Mme and Lepr mRNA levels after adult HFS intake compared with hfs-HFS offspring. In conclusion, maternal HFS diet during lactation influenced the response to an obesogenic diet in the adult progeny. Interestingly, dietary methyl donor supplementation in lactating mothers fed an obesogenic diet reduced liver fat accumulation, but increased adipose tissue storage in adult HFS-fed offspring.
Autores: Mansego, Maria L; Zulet, María de los Ángeles; Campión, Francisco Javier; et al.
Revista: ANALES DE LA REAL ACADEMIA NACIONAL DE FARMACIA
ISSN 1697-4271  Vol. 80  Nº 3  2014  págs. 614 - 623
Mediante una aproximación epigenómica, se analizaron las posibles asociaciones entre los niveles basales en la metilación del ADN y una mejor respuesta a la pérdida de peso después de un programa de intervención nutricional en la población obesa del estudio RESMENA. Esta investigación ha identificado 3 regiones de ADN (genes RGS6, A2BP1 y RASGRF1) que se encuentran diferencialmente metiladas entre sujetos con alta y baja respuesta a la pérdida de peso. Además, estos genes están implicados en la misma ruta metabólica y habían sido previamente significativamente asociados con la obesidad.
Autores: Campión, Francisco Javier; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 70  Nº 2  2014  págs. 603 - 614
Some causal bases of stroke remain unclear, but the nutritional effects on the epigenetic regulation of different genes may be involved. The aim was to assess the impact of epigenetic processes of human tumor necrosis factor (TNF-alpha) and paraoxonase (PON) promoters in the susceptibility to stroke when considering body composition and dietary intake. Twenty-four patients (12 non-stroke/12 stroke) were matched by sex (12 male/12 female), age (mean 7012years old), and BMI (12 normal-weight/12 obese; mean 28.16.7kg/m(2)). Blood cell DNA was isolated and DNA methylation levels of TNF-alpha (-186 to +349bp) and PON (-231 to +250bp) promoters were analyzed by the Sequenom EpiTYPER approach. Histone modifications (H3K9ac and H3K4me3) were analyzed also by chromatin immunoprecipitation in a region of TNF-alpha (-297 to -185). Total TNF-alpha promoter methylation was lower in stroke patients (p<0.001) and showed no interaction with body composition (p=0.807). TNF-alpha and PON total methylation levels correlated each other (r=0.44; p=0.031), especially in stroke patients (r=0.72; p=0.008). The +309 CpG methylation site from TNF-alpha promoter was related to body weight (p=0.027) and the region containing three CpGs (from -170 to -162bp) to the percentage of lipid intake and dietary indexes (p<0.05) in non-stroke patients. The methylation of PON +15 and +241 CpGs was related to body weight (p=0.021), waist circumference (p=0.020), and energy intake (p=0.018), whereas +214 was associated to the quality of the diet (p<0.05) in non-stroke patients. When comparing stroke vs non-stroke patients regarding the histone modifications analyzed at TNF-alpha promoter, no changes were found, although a significant association was identified between circulating TNF-alpha level and H3K9ac with H3K4me3. TNF-alpha and PON promoter methylation levels could be involved in the susceptibility to stroke and obesity outcome, respectively. The dietary intake and body composition may influence this epigenetic regulation in non-stroke patients.
Autores: Milagro FI; San-Cristobal, R.; et al.
Revista: EL FARMACEUTICO
ISSN 0213-7283  Vol. 499  2014  págs. 12 - 24
Autores: de la Garza, Ana Laura Isabel; Etxeberria, Usune; et al.
Revista: FOOD & FUNCTION
ISSN 2042-6496  Vol. 5  Nº 9  2014  págs. 2120 - 2128
Type-2 diabetes is associated with a chronic low-grade systemic inflammation accompanied by an increased production of adipokines/cytokines by obese adipose tissue. The search for new antidiabetic drugs with different mechanisms of action, such as insulin sensitizers, insulin secretagogues and ¿-glucosidase inhibitors, has directed the focus on the potential use of flavonoids in the management of type-2 diabetes. Thirty six diabetic male C57BL/6J db/db mice were fed a standard diet and randomly assigned into four experimental groups: non-treated control, (n = 8); acarbose (5 mg per kg bw, n = 8); helichrysum (1 g per kg bw, n = 10) and grapefruit (0.5 g per kg bw, n = 10) for 6 weeks. The mRNA expression in pancreas, liver and epididymal adipose tissue was determined by RT-PCR. DNA methylation was quantified in epididymal fat using pyrosequencing. Mice supplemented with helichrysum and grapefruit extracts showed a significant decrease in fasting glucose levels (p < 0.05). A possible mechanism of action could be the up-regulation of liver glucokinase (p < 0.05). The antihyperglycemic effect of both extracts was accompanied by decreased mRNA expression of some proinflammatory genes (monocyte chemotactic protein-1, tumor necrosis factor-¿, cyclooxygenase-2, nuclear factor-kappaB) in the liver and epididymal adipose tissue. The CpG3 site of TNF¿, located 5 bp downstream of the transcription start site, showed increased DNA methylation in the grapefruit group compared with the non-treated group (p < 0.01). In conclusion, helichrysum and grapefruit extracts improved hyperglycemia through the regulation of glucose metabolism in the liver and reduction of the expression of proinflammatory genes in the liver and visceral fat. The hypermethylation of TNF¿ in adipose tissue may contribute to reduce the inflammation associated with diabetes and obesity.
Autores: Varela-Guruceaga, M.; Milagro FI; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9  Nº 4  2014  págs. e95100
Caveolin 1 (Cav-1) is an essential constituent of adipocyte caveolae which binds the beta subunit of the insulin receptor (IR) and is implicated in the regulation of insulin signaling. We have found that, during adipocyte differentiation of 3T3-L1 cells the promoter, exon 1 and first intron of the Cav-1 gene undergo a demethylation process that is accompanied by a strong induction of Cav-1 expression, indicating that epigenetic mechanisms must have a pivotal role in this differentiation process. Furthermore, IR, PKB-Akt and Glut-4 expression are also increased during the differentiation process suggesting a coordinated regulation with Cav-1. Activation of Cav-1 protein by phosphorylation arises during the differentiation process, yet in fully mature adipocytes insulin is no longer able to significantly increase Cav-1 phosphorylation. However, these long-term differentiated cells are still able to respond adequately to insulin, increasing IR and PKB-Akt phosphorylation and glucose uptake. The activation of Cav-1 during the adipocyte differentiation process could facilitate the maintenance of insulin sensitivity by these fully mature adipocytes isolated from additional external stimuli. However, under the influence of physiological conditions associated to obesity, such as chronic inflammation and hypoxia, insulin sensitivity would finally be compromised.
Autores: Milagro FI; Marcos, A.; et al.
Revista: NUTRICION HOSPITALARIA
ISSN 0212-1611  Vol. 30  Nº 1  2014  págs. 75 - 83
Background: Some SNPs related to lipid and energy metabolism may be implicated not only in the development of obesity and associated comorbidities, but also in the weight loss response after a nutritional intervention. Objective: In this context, the present study analyzed four SNPs located within four genes known to be associated with obesity and other obesity-related complications, and their putative role in a weight-loss intervention in overweight/obese adolescents. Methods: The study population consisted of 199 overweight/obese adolescents (13-16 yr old) undergoing 10 weeks of a weight loss multidisciplinary intervention: the EVASYON programme (www.estudioevasyon.org). Adolescents were genotyped for 4 SNPs, and anthropometric measurements and biochemical markers were analyzed at the beginning and after the intervention. Results: Interestingly, APOA5(rs662799) was associated with the baseline anthropometric and biochemical outcomes, whereas FTO (rs9939609) seemed to be related with the change of these values after the 10-week intervention. The other two SNPs, located in the CETP (rs1800777) and the APOA1 (rs670) genes, showed important relationships with adiposity markers. Specifically, a combined model including both SNPs turned up to explain up to 24% of BMI-SDS change after 10 weeks of the multidisciplinary intervention, which may contribute to under - stand the weight loss response. Conclusion: Common variants in genes related to lipid and energy metabolism may influence not only biochemical outcomes but also weight loss response after a multidisciplinary intervention carried out in obese/overweight adolescents.
Autores: do-Amaral, C.; Milagro FI; Curi, R.; et al.
Revista: BIOMED RESEARCH INTERNATIONAL
ISSN 2314-6133  Vol. 2014  2014  págs. 675021
Dietary factors modulate gene expression and are able to alter epigenetic signatures in peripheral blood mononuclear cells (PBMC). However, there are limited studies about the effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) on the epigenetic mechanisms that regulate gene expression. This research investigates the effects of n-3-rich fish oil supplementation on DNA methylation profile of several genes whose expression has been reported to be down regulated by n-3 PUFA in PBMC: CD36, FFAR3, CD14, PDK4, and FADS1. Young overweight women were supplemented with fish oil or control in a randomized 8-week intervention trial following a balanced diet with 30% energy restriction. Fatty acid receptor CD36 decreased DNA methylation at CpG + 477 due to energy restriction. Hypocaloric diet-induced weight loss also reduced the methylation percentages of CpG sites located in CD14, PDK4, and FADS1. The methylation patterns of these genes were only slightly affected by the fish oil supplementation, being the most relevant to the attenuation of the weight loss-induced decrease in CD36 methylation after adjusting by baseline body weight. These results suggest that the n-3 PUFA-induced changes in the expression of these genes in PBMC are not mediated by DNA methylation, although other epigenetic mechanisms cannot be discarded.
Autores: Goñi, Leticia; Cuervo, M; Milagro FI; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 7  Nº 4-6  2014  págs. 232 - 242
BACKGROUND/AIMS: Investigation of the genetic makeup may facilitate the implementation of more personalized nutritional interventions. The aims were to examine whether the rs10830963 MTNR1B polymorphism affects weight loss in response to a hypocaloric diet and to find potential gene-gene interplays and gene-diet interactions. METHODS: 167 subjects enrolled in a personalized nutritional intervention for weight loss (3-6 weeks) were examined for anthropometric measurements, dietary habits and physical activity at baseline and at the first follow-up visit. Three polymorphisms, which have previously been associated with body weight regulation, rs10830963 (MTNR1B), rs9939609 (FTO) and rs17782313 (MC4R), were analyzed using the Luminex® 100/200¿ System. RESULTS: After adjusting for covariates, females with the rs10830963 CG/GG genotype showed lower weight loss than those with the CC genotype. In the total population, carriers of variant alleles of both FTO and MC4R showed a significant association with MTNR1B and weight loss outcome. Moreover, among women, higher total protein and animal protein intakes were associated with a lower weight loss in G allele carriers of the MTNR1B variant. CONCLUSIONS: Our data evidenced that rs10830963 MTNR1B polymorphism could be associated with individual differences in weight loss induced by a hypocaloric diet. This association was influenced by FTO and MC4R loci and modified by baseline protein intake.
Autores: Varela-Guruceaga, M.; de Miguel, C; et al.
Revista: OBESITY REVIEWS
ISSN 1467-7881  Vol. 15  Nº Suppl. 2  2014  págs. 40
Autores: Milagro FI; Mansego, M. L.; de Miguel, C; et al.
Revista: MOLECULAR ASPECTS OF MEDICINE
ISSN 0098-2997  Vol. 34  Nº 4  2013  págs. 782 - 812
Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding the importance of the inheritance of these epigenetic marks.
Autores: Milagro FI; Martínez, JA;
Revista: REVISTA CHILENA DE ENDOCRINOLOGIA Y DIABETES
ISSN 0718-493X  Vol. 6  Nº 3  2013  págs. 108 - 114
In the last years, epigenetics is helping to explain the mechanisms non dependent on the genetic sequence by which the nutrients and other environmental factors contribute to modulate gene expression and disease development. Obesity and type 2 diabetes are two diseases that have been linked to changes in epigenetic marks (particularly DNA methylation, covalent modifications of histones and miRNAs). These epigenetic changes appear to be influenced, mainly in the perinatal period but also in adulthood, by environmental factors such as hyperglycemia or the diet. Among the food compounds that have been linked to epigenetic modifications, there are methyl donor groups, excessive or deficient caloric intake, short chain fatty acids, some minerals and antioxidant vitamins, and various compounds of plant origin, as catechins, isoflavones or isothiocyanates. EWAS studies, that analyze the methylation of thousands of CpG sites in thousands of individuals, will contribute in the next years to identify some of the epigenetic marks that can be used as early predictors of metabolic risk, as well as some intimate mechanisms that explain the development of obesity, type 2 diabetes and its complications. Moreover, epigenetic marks, among them the CpG-SNPs, can be heritable but some of them could be potentially reversible. One of the medium-term objectives is to develop drug or diet-related treatments that could delay or even reverse these epigenetic changes.
Autores: Mansego, Maria L; Milagro FI; Campión, Francisco Javier; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 6  Nº 2  2013  págs. 83 - 96
Epigenetic mechanisms are likely to play an important role in the regulation of metabolism and body weight through gene-nutrient interactions. This review focuses on methods for analyzing one of the most important epigenetic mechanisms, DNA methylation, from single nucleotide to global measurement depending on the study goal and scope. In addition, this study highlights the major principles and methods for DNA methylation analysis with emphasis on nutritional applications. Recent developments concerning epigenetic technologies are showing promising results of DNA methylation levels at a single-base resolution and provide the ability to differentiate between 5-methylcytosine and other nucleotide modifications such as 5-hydroxymethylcytosine. A large number of methods can be used for the analysis of DNA methylation such as pyrosequencing (TM), primer extension or real-time PCR methods, and genome-wide DNA methylation profile from microarray or sequencing-based methods. Researchers should conduct a preliminary analysis focused on the type of validation and information provided by each technique in order to select the best method fitting for their nutritional research interests.
Autores: Cordero, Paúl; Campión, Francisco Javier; et al.
Revista: GENES AND NUTRITION
ISSN 1555-8932  Vol. 8  Nº 1  2013  págs. 105-113
Non-alcoholic fatty liver disease (NAFLD) is one of the first hepatic manifestations of metabolic syndrome, whose progression can lead to cirrhosis and hepatic carcinoma. Interestingly, methyl donor supplementation could improve obesogenic diet-induced hepatic triglyceride accumulation. The aim of this research is to describe methyl donor effects on a high-fat-sucrose (HFS) diet in both sexes and epigenetic changes induced on fatty acid synthase (FASN) promoter methylation pattern as well as gene expression of NAFLD key metabolic genes. Twenty-four male and 28 female Wistar rats were assigned to three dietary groups: control, HFS, and HFS supplemented with methyl donors (choline, betaine, vitamin B12, and folic acid). After 8 weeks of treatment, somatic, biochemical, mRNA, and epigenetic measurements were performed. Rats fed the HFS diet presented an overweight phenotype and alterations in plasma biochemical measurements. Methyl donor supplementation reverted the HFS-diet-induced hepatic triglyceride accumulation. Analysis of FASN promoter cytosine methylation showed changes in both sexes due to the obesogenic diet at -1,096, -780, -778, and -774 CpG sites with respect to the transcriptional start site. Methyl donor supplementation modified DNA methylation at -852, -833, -829, -743, and -733 CpGs depending on the sex. RT-PCR analysis confirmed that FASN expression tended to be altered in males. Our findings reinforce the hypothesis that methyl donor supplementation can prevent hepatic triglyceride accumulation induced by obesogenic diets in both sexes. Changes in liver gene expression profile and epigenetic-mediated mechanisms related to FASN DNA hypermethylation could be involved in methyl donor-induced NAFLD improvement.
Autores: Cordero, Paúl; Milagro FI; Campión, Francisco Javier; et al.
Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067  Vol. 14  Nº 12  2013  págs. 24422 - 24437
Maternal perinatal nutrition may program offspring metabolic features. Epigenetic regulation is one of the candidate mechanisms that may be affected by maternal dietary methyl donors intake as potential controllers of plasma homocysteine levels. Thirty-two Wistar pregnant rats were randomly assigned into four dietary groups during lactation: control, control supplemented with methyl donors, high-fat-sucrose and high-fat-sucrose supplemented with methyl donors. Physiological outcomes in the offspring were measured, including hepatic mRNA expression and global DNA methylation after weaning. The newborns whose mothers were fed the obesogenic diet were heavier longer and with a higher adiposity and intrahepatic fat content. Interestingly, increased levels of plasma homocysteine induced by the maternal high-fat-sucrose dietary intake were prevented in both sexes by maternal methyl donors supplementation. Total hepatic DNA methylation decreased in females due to maternal methyl donors administration, while Dnmt3a hepatic mRNA levels decreased accompanying the high-fat-sucrose consumption. Furthermore, a negative association between Dnmt3a liver mRNA levels and plasma homocysteine concentrations was found. Maternal high-fat-sucrose diet during lactation could program offspring obesity features, while methyl donors supplementation prevented the onset of high hyperhomocysteinemia. Maternal dietary intake also affected hepatic DNA methylation metabolism, which could be linked with the regulation of the methionine-homocysteine cycle.
Autores: Milagro FI; Miranda, J.; Portillo, M. P.; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 8  Nº 1  2013 
Introduction: MicroRNAs (miRNAs) are being increasingly studied in relation to energy metabolism and body composition homeostasis. Indeed, the quantitative analysis of miRNAs expression in different adiposity conditions may contribute to understand the intimate mechanisms participating in body weight control and to find new biomarkers with diagnostic or prognostic value in obesity management. Objective: The aim of this study was the search for miRNAs in blood cells whose expression could be used as prognostic biomarkers of weight loss. Methods: Ten Caucasian obese women were selected among the participants in a weight-loss trial that consisted in following an energy-restricted treatment. Weight loss was considered unsuccessful when <5% of initial body weight (non-responders) and successful when >5% (responders). At baseline, total miRNA isolated from peripheral blood mononuclear cells (PBMC) was sequenced with SOLiD v4. The miRNA sequencing data were validated by RT-PCR. Results: Differential baseline expression of several miRNAs was found between responders and non-responders. Two miRNAs were up-regulated in the non-responder group (mir-935 and mir-4772) and three others were down-regulated (mir-223, mir-224 and mir-376b). Both mir-935 and mir-4772 showed relevant associations with the magnitude of weight loss, although the expression of other transcripts (mir-874, mir-199b, mir-766, mir-589 and mir-148b) also correlated with weight loss. Conclusions: This research addresses the use of high-throughput sequencing technologies in the search for miRNA expression biomarkers in obesity, by determining the miRNA transcriptome of PBMC. Basal expression of different miRNAs, particularly mir-935 and mir-4772, could be prognostic biomarkers and may forecast the response to a hypocaloric diet.
Autores: Etxeberria U; de la Garza, Ana Laura Isabel; Martínez, JA; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 69  Nº 3  2013  págs. 613 - 623
Metabolomics is a high-throughput tool that quantifies and identifies the complete set of biofluid metabolites. This "omics" science is playing an increasing role in understanding the mechanisms involved in disease progression. The aim of this study was to determine whether a nontargeted metabolomic approach could be applied to investigate metabolic differences between obese rats fed a high-fat sucrose (HFS) diet for 9 weeks and control diet-fed rats. Animals fed with the HFS diet became obese, hyperleptinemic, hyperglycemic, hyperinsulinemic, and resistant to insulin. Serum samples of overnight-fasted animals were analyzed by (1)H NMR technique, and 49 metabolites were identified and quantified. The biochemical changes observed suggest that major metabolic processes like carbohydrate metabolism, ß-oxidation, tricarboxylic acid cycle, Kennedy pathway, and folate-mediated one-carbon metabolism were altered in obese rats. The circulating levels of most amino acids were lower in obese animals. Serum levels of docosahexaenoic acid, linoleic acid, unsaturated n-6 fatty acids, and total polyunsaturated fatty acids also decreased in HFS-fed rats. The circulating levels of urea, six water-soluble metabolites (creatine, creatinine, choline, acetyl carnitine, formate, and allantoin), and two lipid compounds (phosphatidylcholines and sphingomyelin) were also significantly reduced by the HFS diet intake. This study offers further insight of the possible mechanisms implicated in the development of diet-induced obesity. It suggests that the HFS diet-induced hyperinsulinemia is responsible for the decrease in the circulating levels of urea, creatinine, and many amino acids, despite an increase in serum glucose levels.
Autores: Uriarte, G.; Milagro FI; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 69  Nº 3  2013  págs. 601 - 611
The aim of the study was to analyze the phenotypic and epigenetic changes induced by the shift to a chow diet after an obesogenic environment. Animals were randomized to fed chow (control group) or high-fat-sucrose diet (HFS). After 10 weeks, half of the rats fed with HFS diet were reassigned to a chow diet (rest group) while the other half continued with the obesogenic diet (HFS group) until week 20. Changes in fat content, biochemical profile, and DNA methylation levels of several gene promoters from retroperitoneal adipocytes were analyzed. HFS diet intake for 10 weeks induced obese phenotype in the animals, increasing body weight and fat content. These effects were maintained until the end of the trial in HFS group, where an increase in liver fat content, a modification of lipid profile, and retroperitoneal adipose tissue hypertrophy were also observed. Changing the dietary pattern reversed these parameters. Epigenetic analysis showed that HFS diet intake for 20 weeks hypermethylated several CpG sites (6.7 and 29.30) and hypomethylated CpG site 15 from leptin gene promoter. Moreover, the obesogenic diet also hypomethylated CpG site 1 from Fasn (fatty acid synthase) gene promoter, without changes on Ppargc1a (peroxisome proliferator-activated receptor gamma coactivator 1-alpha), Srebf1 (sterol regulatory element-binding transcription factor 1), and aquaporin 7. Shifting to a chow diet reverted HFS-induced DNA methylation levels of some CpG sites of leptin promoter. Changing the dietary pattern hypomethylated a CpG site of Srebf1 and hypermethylated other CpGs on Ppargc1a and Fasn promoter. This study shed light on the reversibility of phenotypical and epigenetic changes induced by a HFS diet intake.
Autores: San-Cristobal, R.; Milagro FI; Martínez, JA;
Revista: ACADEMY OF NUTRITION AND DIETETICS. JOURNAL
ISSN 2212-2672  Vol. 113  Nº 11  2013  págs. 1447 - 1454
Autores: Crujeiras, Ana Belén; Campión, Francisco Javier; et al.
Revista: REGULATORY PEPTIDES
ISSN 0167-0115  Vol. 186  2013  págs. 1 - 6
Specific methylation of appetite-related genes in leukocytes could serve as a useful biomarker to predict weight regain after an energy restriction program. We aimed to evaluate whether the pre-intervention DNA methylation patterns involved in the epigenetic control of appetite-regulatory genes in leukocytes are associated with the weight regain process. Eighteen men who lost ¿5% of body weight after an 8-week nutritional intervention were categorized as "regainers" (¿10% weight regain) and "non-regainers" (<10% weight regain) 32weeks after stopping dieting. At baseline, leukocytes were isolated and DNA was analyzed for epigenetic methylation patterns of appetite-related gene promoters by MALDI-TOF mass spectrometry. Regainers showed higher methylation levels than non-regainers in proopiomelanocortin (POMC) CpG sites +136bp and +138bp (fold change from non-regainers=26%; p=0.020) and lower methylation of the whole analyzed region of neuropeptide Y (NPY; fold change from non-regainers=-22%; p=0.033), as well as of several individual NPY-promoter CpG sites. Importantly, total baseline NPY methylation was associated with weight-loss regain (r=-0.76; p<0.001), baseline plasma ghrelin levels (r=0.60; p=0.011) and leptin/ghrelin ratio (r=-0.52; p=0.046). Lower methylation levels of POMC CpG sites +136bp and +138bp were associated with success in weight-loss maintenance (odds ratio=0.042 [95% CI 0.01-0.57]; p=0.018), whereas lower total methylation levels in NPY promoter were associated with higher risk of weight regain (odds ratio=14.0 [95% CI 1.13-172]; p=0.039). Therefore, the study of leukocyte methylation levels reflects a putative epigenetic regulation of NPY and POMC, which might be implicated in the weight regain process and be used as biomarkers for predicting weight regain after dieting.
Autores: Hermsdorff, H.H.; Mansego, Maria L; Campión, Francisco Javier; et al.
Revista: CYTOKINE
ISSN 1043-4666  Vol. 64  Nº 1  2013  págs. 265 - 271
The aim of this article is to assess the potential relationships between TNFalpha gene promoter methylation in peripheral white blood cells and central adiposity (truncal fat), metabolic features and dietary fat intake. A group of 40 normal-weight young women (213y; BMI 21.01.7kg/m(2)) was included in this cross-sectional study. Anthropometric, biochemical and dietary data were assessed using validated procedures. DNA from white blood cells was isolated and 5-methylcytosine levels of the CpGs sites present in TNFalpha gene promoter (from -170 to +359 pb) were analyzed by Sequenom EpiTyper. Those women with high truncal fat (¿52.3%) showed lower 5-methylcytosine levels (P<0.05) in the site CpG13 (at position +207) and CpG19 (+317 pb) of the TNFalpha gene promoter when were compared to women with lower truncal adiposity. The methylation levels of CpG13 were also correlated with circulating TNFalpha levels, which were higher in those women with greater truncal adiposity. In a linear regression model, truncal fat, HDL-cholesterol, insulin, plasma TNFalpha, and daily n-6 PUFA intake explained the methylation levels of CpG13 site +207 by 48% and the average of CpG13 and CpG19 by 43% (P<0.001). In conclusion, women with higher truncal fat showed lower methylation levels of TNFalpha promoter in peripheral white blood cells and higher plasma TNFalpha concentrations. DNA methylation levels of TNFalpha promoter were associated with some metabolic features and with n-6 PUFA intake, suggesting a complex nutriepigenomic network in the regulation of this recognized pro-inflammatory marker.
Autores: de la Garza, Ana Laura Isabel; Etxeberria, Usune; Lostao MP; et al.
Revista: JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
ISSN 0021-8561  Vol. 61  Nº 49  2013  págs. 12012 - 12019
Several plant extracts rich in flavonoids have been reported to improve hyperglycemia by inhibiting digestive enzyme activities and SGLT1-mediated glucose uptake. In this study, helichrysum ( Helichrysum italicum ) and grapefruit ( Citrus × paradisi ) extracts inhibited in vitro enzyme activities. The helichrysum extract showed higher inhibitory activity of ¿-glucosidase (IC50 = 0.19 mg/mL) than ¿-amylase (IC50 = 0.83 mg/mL), whereas the grapefruit extract presented similar ¿-amylase and ¿-glucosidase inhibitory activities (IC50 = 0.42 mg/mL and IC50 = 0.41 mg/mL, respectively). Both extracts reduced maltose digestion in noneverted intestinal sacs (57% with helichrysum and 46% with grapefruit). Likewise, both extracts inhibited SGLT1-mediated methylglucoside uptake in Caco-2 cells in the presence of Na+ (56% of inhibition with helichrysum and 54% with grapefruit). In vivo studies demonstrated that helichrysum decreased blood glucose levels after an oral maltose tolerance test (OMTT), and both extracts reduced postprandial glucose levels after the oral starch tolerance test (OSTT). Finally, both extracts improved hyperinsulinemia (31% with helichrysum and 50% with grapefruit) and HOMA index (47% with helichrysum and 54% with grapefruit) in a dietary model of insulin resistance in rats. In summary, helichrysum and grapefruit extracts improve postprandial glycemic control in rats, possibly by inhibiting ¿-glucosidase and ¿-amylase enzyme activities and decreasing SGLT1-mediated glucose uptake.
Autores: Steemburgo, T.; Azevedo, M.J.; Gross, J.L.; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 6  Nº 2  2013  págs. 97 - 106
Background/Aims: The common polymorphism in the FTO gene (rs9939609) has been associated with obesity, type 2 diabetes, and appetite regulation. The aim of this study was to evaluate possible associations of FTO rs9939609 with dietary factors in patients with type 2 diabetes. Methods: This was a cross-sectional study of 236 patients with type 2 diabetes (age 60.0 +/- 10.3 years; diabetes duration 12.7 +/- 8.2 years; 53.4% females) who were genotyped for FTO rs9939609. Patients underwent clinical and laboratory evaluations and 3-day weighed diet records. Data on dietary intake were categorized as high or low, based on median values. Results: The AA genotype in the FTO gene was positively associated with high fat (>34% energy; OR = 2.17; 95% CI 1.02-4.63) and low fiber intakes (<16 g/day; OR = 2.42; 95% CI 1.05-5.57), adjusted for gender, BMI, total energy intake, systolic blood pressure, and HbA1c. When gender was taken into account, AA females had higher fat (37.4 +/- 5.3 vs. 32.6 +/- 7.5 and 32.2 +/- 6.2% energy; p = 0.005) and lower fiber intakes (12.4 +/- 4.4 vs. 15.1 +/- 6.3 and 16.7 +/- 5.6 g/day; p = 0.023) than patients with TT and AT genotypes. Multiple logistic regression models confirmed female associations for high fat (OR = 9.73; 95% CI 2.12-44.66) and low fiber intakes (OR = 4.28; 95% CI 1.14-16.06; p < 0.05 for all models). Conclusions: Patients with type 2 diabetes, who were carriers of the AA genotype of the FTO rs9939609, had increased fat and decreased fiber consumption, independently of BMI.
Autores: Boqué, Noemi; Campión, Francisco Javier; et al.
Revista: JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE
ISSN 0022-5142  Vol. 93  Nº 5  2013  págs. 1226 - 1232
Background Polyphenols have been reported to prevent chronic diseases such as cardiovascular diseases, cancers, diabetes and neurodegenerative diseases. The objective of the study was to conduct a screening for potential anti-obesity polyphenolic plant extracts using a diet-induced animal model. Rats were fed a high-fat-sucrose (HFS) diet with or without supplementation of different polyphenolic plant extracts (almond, apple, cinnamon, orange blossom, hamamelis, lime blossom, grape vine, and birch) for 5664 days. Results Body weight gain was lower in rats supplemented with apple, cinnamon, hamamelis and birch extracts as compared to HFS non-supplemented group. Moreover, apple and cinnamon extracts prevented the increase in fat mass promoted by the HFS diet. Insulin resistance, estimated by the homostatic model assessmentinsulin resistance (HOMA-IR) index, was reduced in rats fed apple, cinnamon, hamamelis and birch extracts. Apple extract also prevented the HFS-induced hyperglycaemia and hyperleptinaemia. Conclusion Only apple and cinnamon extracts were finally considered as potentially important anti-obesogenic extracts, due to their body fat-lowering effects, while the improvement of obesity-related metabolic complications by apple polyphenols highlights this extract as a promising functional food ingredient for the management of obesity and its metabolic complications.
Autores: Boqué, Noemi; de la Garza, Ana Laura Isabel; et al.
Revista: MOLECULAR NUTRITION AND FOOD RESEARCH
ISSN 1613-4125  Vol. 57  Nº 8  2013  págs. 1473 - 1478
his study was conducted to determine the mechanisms implicated in the beneficial effects of apple polyphenols (APs) against diet-induced obesity in Wistar rats, described in a previous study from our group. Supplementation of high-fat sucrose diet with AP prevented adiposity increase by inhibition of adipocyte hypertrophy. Rats supplemented with AP exhibited improved glucose tolerance while adipocytes isolated from these rats showed an enhanced lipolytic response to isoproterenol. AP intake led to reduced Lep, Plin, and sterol regulatory element binding transcription factor 1 (Srebf1) mRNA levels and increased aquaporin 7 (Aqp7), adipocyte enhancer binding protein 1 (Aebp1), and peroxisome proliferator-activated receptor gamma co-activator 1 alpha (Ppargc1a) mRNA levels in epididymal adipocytes. In addition, we found different methylation patterns of Aqp7, Lep, Ppargc1a, and Srebf1 promoters in adipocytes from apple-supplemented rats compared to high-fat sucrose fed rats. The administration of AP protects against body weight gain and fat deposition and improves glucose tolerance in rats. We propose that AP exerts the antiobesity effects through the regulation of genes involved in adipogenesis, lipolysis, and fatty acid oxidation, in a process that could be mediated in part by epigenetic mechanisms.
Autores: Martínez, JA; Etxeberria U; Galar, Alicia; et al.
Revista: REJUVENATION RESEARCH
ISSN 1549-1684  Vol. 16  Nº 5  2013  págs. 435 - 437
Abstract Mendelsohn and Larrick have recently discussed in a recent article in Rejuvenation Research that dietary modifications of the gut microbiota affect the risk for cardiovascular disease. In this context, dietary patterns and single specific nutrients appear to produce singular consequences on the gut microbiota, subsequently impacting on maintenance of well-being and disease onset or evolution, whose intimate influences and mechanisms are now starting to be disentangled. Thus, the consumption of dietary fiber and particular polysaccharides affects colonic fermentation processes involving short-chain fatty acid production, accompanying changes in the environmental pH, inhibiting Bacteroides spp., and rising levels of butyrate-producing Gram-positive bacteria. This scenario may contribute to the design of novel therapeutic approaches to manipulate gut microbiota to treat cardiovascular diseases and obesity. Indeed, cardiovascular risk may be indirectly dependent on pathways associated with microbe-induced obesity or diabetes through inflammation. Diverse components of the diet, including bioactive molecules with bactericidal functions, such as polyphenols, may play a role on intestinal mucosa inflammation and permeability and contribute to explaining the mutual interactions between obesity, diabetes, and adverse cardiovascular events.
Autores: Etxeberría, U.; Fernández-Quintela, A.; Milagro FI; et al.
Revista: JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
ISSN 0021-8561  Vol. 61  Nº 40  2013  págs. 9517 - 9533
Gut microbiota plays a key role in host physiology and metabolism. Indeed, the relevance of a well-balanced gut microbiota composition to an individual's health status is essential for the person's well-being. Currently, investigations are focused on analyzing the effects of pre- and probiotics as new therapeutic tools to counteract the disruption of intestinal bacterial balance occurring in several diseases. Polyphenols exert a wide range of beneficial health effects. However, although specific attention has been paid in recent years to the function of this "biological entity" in the metabolism of polyphenols, less is known about the modulatory capacity of these bioactive compounds on gut microbiota composition. This review provides an overview of the latest investigations carried out with pure polyphenols, extracts rich in polyphenols, and polyphenol-rich dietary sources (such as cocoa, tea, wine, soy products, and fruits) and critically discusses the consequences to gut microbiota composition which are produced.
Autores: de la Garza, Ana Laura Isabel; Batlle MA ; et al.
Revista: STRESS
ISSN 1607-8888  Vol. 16  Nº 2  2013  págs. 220 - 232
Stress during pregnancy can induce metabolic disorders in adult offspring. To analyze the possible differential response to a high-fat-sucrose (HFS) diet in offspring affected by prenatal stress (PNS) or not, pregnant Wistar rats (n = 11) were exposed to a chronic mild stress during the third week of gestation. The aim of this study was to model a chronic depressive-like state that develops over time in response to exposure of rats to a series of mild and unpredictable stressors. Control dams (n = 11) remained undisturbed. Adult offspring were fed chow or HFS diet (20% protein, 35% carbohydrate, 45% fat) for 10 weeks. Changes in adiposity, biochemical profile, and retroperitoneal adipose tissue gene expression by real-time polymerase chain reaction were analyzed. An interaction was observed between HFS and PNS concerning visceral adiposity, with higher fat mass in HFS-fed stressed rats, statistically significant only in females. HFS modified lipid profile and increased insulin resistance biomarkers, while PNS reduced insulin concentrations and the homeostasis model assessment index. HFS diet increased gene (mRNA) expression for leptin and apelin and decreased cyclin-dependent kinase inhibitor 1A and fatty acid synthase (Fasn), whereas PNS increased Fasn and stearoyl-CoA desaturase1. An interaction between diet and PNS was observed for adiponutrin (Adpn) and peroxisome proliferator-activated receptor-gamma coactivator1-alpha (Ppargc1a) gene expression: Adpn was increased by the PNS only in HFS-fed rats, whereas Ppargc1a was increased by the PNS only in chow-fed rats. From these results, it can be concluded that experience of maternal stress during intrauterine development can enhance predisposition to obesity induced by a HFS diet intake.
Autores: Campión, Francisco Javier; Milagro FI; et al.
Revista: FASEB JOURNAL
ISSN 0892-6638  Vol. 27  Nº 6  2013  págs. 2504 - 2512
In recent years, epigenetic markers emerged as a new tool to understand the influence of lifestyle factors on obesity phenotypes. Adolescence is considered an important epigenetic window over a human¿s lifetime. The objective of this work was to explore baseline changes in DNA methylation that could be associated with a better weight loss response after a multidisciplinary intervention program in Spanish obese or overweight adolescents. Overweight or obese adolescents (n=107) undergoing 10 wk of a multidisciplinary intervention for weight loss were assigned as high or low responders to the treatment. A methylation microarray was performed to search for baseline epigenetic differences between the 2 groups (12 subjects/group), and MALDI-TOF mass spectrometry was used to validate (n=107) relevant CpG sites and surrounding regions. After validation, 5 regions located in or near AQP9, DUSP22, HIPK3, TNNT1, and TNNI3 genes showed differential methylation levels between high and low responders to the multidisciplinary weight loss intervention. Moreover, a calculated methylation score was significantly associated with changes in weight, BMI-SDS, and body fat mass loss after the treatment. In summary, we have identified 5 DNA regions that are differentially methylated depending on weight loss response. These methylation changes may help to better understand the weight loss response in obese adolescents.
Autores: Milagro FI; Martínez, JA;
Revista: ENDOCRINOLOGIA Y NUTRICION
ISSN 1575-0922  Vol. 60  Nº Supl. 1  2013  págs. 12 - 14
Autores: de la Garza, Ana Laura Isabel; Etxeberria, U.; Milagro FI; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 63  Nº Suppl. 1  2013  págs. 244
Autores: Varela, M.; Milagro FI; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 63  Nº Suppl. 1  2013  págs. 378
Autores: Campión, Francisco Javier; Milagro FI; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 63  Nº Suppl. 1  2013  págs. 375
Autores: González-Muniesa, P; Cordero, Paúl; Campión, Francisco Javier; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 6  Nº Suppl.1  2013  págs. 51
Autores: Hermsdorff, H. H. M.; Milagro FI; Campión, Francisco Javier; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 6  Nº 4-5  2013  págs. 222 - 223
Autores: Abete, Itziar; Milagro FI; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 63  Nº Suppl. 1  2013  págs. 376 - 377
Autores: González-Muniesa, P; do-Amaral, C. L.; Milagro FI; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 6  Nº Suppl. 1  2013  págs. 51
Autores: Varela M; de Miguel, C; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 6  2013  págs. 237
Autores: Etxeberria, U.; Milagro FI; Arias, N.; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 63  Nº Suppl. 1  2013  págs. 1264
Autores: Miranda, J.; Milagro FI; Fernández-Quintela, A.; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 6  Nº Suppl. 1  2013  págs. 121
Autores: San Cristóbal, R.; Goñi, Leticia; Milagro FI; et al.
Revista: ANNALS OF NUTRITION AND METABOLISM
ISSN 0250-6807  Vol. 63  Nº Suppl. 1  2013  págs. 378
Autores: Abete, Itziar; Milagro FI; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 6  Nº 4-5  2013  págs. 219
Autores: Alves NEG; Valdés, SE; Silveira CMM; et al.
Revista: THE OPEN NUTRACEUTICALS JOURNAL
ISSN 1876-3960  Vol. 5  2012  págs. 193 - 206
Obesity is recognised as a condition of low-grade chronic inflammation resulting from macrophage infiltration of adipose tissue and activation of inflammatory pathways by oxidative stress mechanisms that lead to the development of insulin resistance. Various natural bioactive compounds (NBCs) with anti-inflammatory and anti-oxidant effects may im-prove adipocyte dysfunction associated with metabolic syndrome. The present review focuses on the effects of phenolic compounds, n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) and lipoic acid (LA) on the pathophysiological mechanisms of obesity. In this review, a total of 120 studies were included, and data thus obtained reflect beneficial physiological effects of n-3 LC-PUFA, LA and different phenolic compounds, including kaempferol, luteolin, apigenin, quercetin, resveratrol, curcumin, catechins, phenolic acids, in the prevention and/or attenuation of metabolic disturbances associated with obesity. Additionally, information from clinical studies provides new insights for defining the dose-response relationship of dietary compounds, necessary time of exposure and potential side effects of these NBCs in the treatment of obesity and indicates further study is needed to verify these relationships.
Autores: Martínez, JA; Cordero, Paúl; Campión, Francisco Javier; et al.
Revista: PROCEEDINGS OF THE NUTRITION SOCIETY
ISSN 0029-6651  Vol. 71  Nº 2  2012  págs. 276 - 283
Autores: Martisová, Eva; Solas, Maite; Guereñu, Gorka; et al.
Revista: CURRENT ALZHEIMER RESEARCH
ISSN 1567-2050  Vol. 9  Nº 7  2012  págs. 822 - 829
The objective of the present work was to study a purported involvement of stress in amyloid pathology through the modulation of BACE expression. Early-life stressed rats (maternal separation, MS) showed significant increases in corticosterone levels, BACE expression and Aß levels. The CpG7 site of the BACE promoter was significantly hypomethylated in MS, and corticosterone levels negatively correlated to the methylation status of CpG7. The activation of the stress-activated protein kinase JNK was also increased in MS rats. In SHSY-5Y neuroblastoma cells, corticosterone induced a rapid increase in BACE expression that was abolished by specific inhibiton of JNK activation or by spironolactone, a mineralocorticoid receptor antagonist, but not by mifepristone, a glucocorticoid receptor antagonist. Corticosterone was also able to increase pJNK expression and this effect was fully reverted by spironolactone. Mice chronically treated with corticosterone showed increased BACE and pJNK expression. These increases were reverted by treatment with spironolactone or with a JNK inhibitor. It is suggested that increased corticosterone levels associated to stress lead to increase BACE transcription both through epigenetic mechanisms and activation of JNK.
Autores: Martisová, Eva; Milagro FI; et al.
Revista: DISEASE MODELS AND MECHANISMS
ISSN 1754-8403  Vol. 5  Nº 5  2012  págs. 691 - 697
An early-life adverse environment has been implicated in the susceptibility to different diseases in adulthood, such as mental disorders, diabetes and obesity. We analyzed the effects of a high-fat sucrose (HFS) diet for 35 days in adult female rats that had experienced 180 minutes daily of maternal separation (MS) during lactancy. Changes in the obesity phenotype, biochemical profile, levels of glucocorticoid metabolism biomarkers, and the expression of different obesity- and glucocorticoid-metabolism-related genes were analyzed in periovaric adipose tissue. HFS intake increased body weight, adiposity and serum leptin levels, whereas MS decreased fat pad masses but only in rats fed an HFS diet. MS reduced insulin resistance markers but only in chow-fed rats. Corticosterone and estradiol serum levels did not change in this experimental model. A multiple gene expression analysis revealed that the expression of adiponutrin (Adpn) was increased owing to MS, and an interaction between HFS diet intake and MS was observed in the mRNA levels of leptin (Lep) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Ppargc1a). These results revealed that early-life stress affects the response to an HFS diet later in life, and that this response can lead to phenotype and transcriptomic changes.
Autores: Milagro FI; Gómez-Abellan P; Campión, Francisco Javier; et al.
Revista: CHRONOBIOLOGY INTERNATIONAL
ISSN 0742-0528  Vol. 29  Nº 9  2012  págs. 1180 - 1194
The circadian clock system instructs 24-h rhythmicity on gene expression in essentially all cells, including adipocytes, and epigenetic mechanisms may participate in this regulation. The aim of this research was to investigate the influence of obesity and metabolic syndrome (MetS) features in clock gene methylation and the involvement of these epigenetic modifications in the outcomes. Sixty normal-weight, overweight and obese women followed a 16-weeks weight reduction program. DNA methylation levels at different CpG sites of CLOCK, BMAL1 and PER2 genes were analyzed by Sequenom's MassARRAY in white blood cells obtained before the treatment. Statistical differences between normal-weight and overweight + obese subjects were found in the methylation status of different CpG sites of CLOCK (CpGs 1, 5-6, 8 and 11-14) and, with lower statistical significance, in BMAL1 (CpGs 6-7, 8, 15 and 16-17). The methylation pattern of different CpG sites of the three genes showed significant associations with anthropometric parameters such as body mass index and adiposity, and with a MetS score. Moreover, the baseline methylation levels of CLOCK CpG 1 and PER2 CpGs 2-3 and 25 correlated with the magnitude of weight loss. Interestingly, the percentage of methylation of CLOCK CpGs 1 and 8 showed associations with the intake of monounsaturated and polyunsaturated fatty acids. This study demonstrates for the first time an association between methylation status of CpG sites located in clock genes (CLOCK, BMAL1 and PER2) with obesity, MetS and weight loss. Moreover, the methylation status of different CpG sites in CLOCK and PER2 could be used as biomarkers of weight-loss success, particularly CLOCK CPGs 5-6.
Autores: Steemburgo , T; de Azebedo, MJ; Gross, JL; et al.
Revista: Journal of Renal Nutrition
ISSN 1051-2276  Vol. 22  Nº 2  2012  págs. 228 - 236
Autores: Battle MA; de la Garza, Ana Laura Isabel; et al.
Revista: NEUROENDOCRINOLOGY
ISSN 0028-3835  Vol. 96  Nº 3  2012  págs. 249 - 260
Disturbances in the prenatal period are linked to metabolic disorders in adulthood, implying the hypothalamic systems of appetite and energy balance regulation. In order to analyze the central effects of a high-fat-sucrose (HFS) diet in prenatally stressed (PNS) female adult rats, Wistar dams were exposed to chronic-mild-stress during the third week of gestation and were then compared with unstressed controls. Adult female offspring were fed a chow or HFS diet for 10 weeks. Changes in body weight, adiposity as well as expression and methylation levels of selected hypothalamic genes were analyzed. PNS induced lower birthweight and body length with no changes in body fat mass. After the HFS diet, the expected overweight model was observed accompanied by higher adiposity and insulin resistance, which was worsened by PNS. The stress model induced higher energy intake in adulthood. Hypothalamic gene expression analysis revealed that the HFS diet decreased Slc6a3 (dopamine active transporter), NPY (neuropeptide Y) and IR (insulin receptor) and increased POMC (pro-opiomelanocortin). Hypothalamic DNA methylation levels in the promoter region of Slc6a3 revealed that Slc6a3 was hypermethylated by the HFS diet in CpG site -53 bp to the transcription start site. HFS diet also hypermethylated CpG site -167 bp of the POMC promoter only in nonstressed animals. No correlations were found between gene expression and DNA methylation levels. These results imply that early-life stress in females increased predisposition to diet-induced obesity in adulthood.
Autores: Cordero, Paúl; Milagro FI; et al.
Revista: JOURNAL OF ENDOCRINOLOGICAL INVESTIGATION
ISSN 0391-4097  Vol. 35  Nº 11  2012  págs. 981 - 986
BACKGROUND: The aim of this research was to analyze the influence of the maternal dietary intake before pregnancy, as well as the parental impact on the response to a transgenerational high-fat-diet in rats. METHODS: Ten female Wistar rats were fed a standard or a high-fat-sucrose (HFS) diet in the 8 weeks prior to pregnancy. Adult offsprings were assigned to a control or obesogenic diet for 8 weeks. Then, rat tissues and plasma samples were collected for analyzing tissue weight, liver triglycerides, and biochemical parameters such as triglycerides, HDL cholesterol, glucose, and insulin levels. RESULTS: The offspring of rats fed a HFS diet gained less weight when they were fed the same diet than those fed a HFS diet combined with maternal control diet. Insulin levels were higher in rats fed a HFS diet (p<0.05) in both sexes; however, maternal HFS diet reversed, partially in males and total- ly in females, this hormonal imbalance. In male newborns, diet-induced maternal weight gain before pregnancy significantly influenced visceral (R 2 =0.373) and subcutaneous (R 2 =0.239) adipose deposition as well as liver weight (R 2 =0.130). Paternal genetic make-up was also a relevant factor affecting adiposity in both sexes (R 2 =0.333 in visceral fat; R 2 =0.183 in subcutaneous fat in males, and 0.292 and 0.282, respectively in females) as well as plasma triglycerides (R 2 =0.193 in males and R 2 =0.251 in females). CONCLUSIONS: The genetic parental background and pre-natal maternal diet are important factors in the response to a hypercaloric diet and affect body composition and glucose homeostasis traits, including insulin secretion and homeostatic model assessment index.
Autores: de-Lorenzo, D.; Milagro FI; Martínez, JA;
Revista: AULA DE LA FARMACIA
ISSN 1697-543X  Vol. 8  Nº 93  2012  págs. 61 - 72
Autores: Gómez-Zorita , S; Fernández-Quintela , A; Macarulla, MT; et al.
Revista: BRITISH JOURNAL OF NUTRITION
ISSN 0007-1145  Vol. 107  Nº 2  2012  págs. 202 - 210
Non-alcoholic fatty liver disease (NAFLD) is one of the most common manifestations of chronic liver disease worldwide. The aim of the present study was to assess the effect of resveratrol on liver fat accumulation, as well as on the activity of those enzymes involved in lipogenesis and fatty acid oxidation in fa/fa Zucker rats. A total of thirty rats were assigned to three experimental groups and orally treated with resveratrol for 6 weeks, or without resveratrol (C: control group; RSV15 group: 15 mg/kg body weight per d; RSV45 group: 45 mg/kg body weight per d). Liver histological analysis was performed by microscopy. Levels of hepatic carnitine palmitoyltransferase-Ia (CPT-Ia), acyl-coenzyme A oxidase (ACO), fatty acid synthase, glucose-6-phosphate dehydrogenase and malic enzyme were assessed by spectrophotometry, and acetyl-CoA carboxylase was assessed by radiometry. Commercial kits were used to determine serum TAG, NEFA, total HDL and non-HDL-cholesterol, glycerol, ketonic bodies, glucose, insulin, adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), hepatic TAG, thiobarbituric acid reactive substrates, GSH (GSSG) and superoxide dismutase. Resveratrol reduced liver weight and TAG content. It did not modify the activity of lipogenic enzymes but it did increase CPT-Ia and ACO activities. NEFA and ALP were reduced in both resveratrol-treated groups. AST/GOT was reduced only by the lowest dose. ALT/GPT, TAG and adiponectin remained unchanged. Resveratrol reduced liver oxidative stress. This study demonstrates that resveratrol can protect the liver from NAFLD by reducing fatty acid availability. Moreover, resveratrol also protects liver from oxidative stress.
Autores: García, Diego Fernando; Campión, Francisco Javier; Arellano, AV; et al.
Revista: EXPERIMENTAL BIOLOGY AND MEDICINE
ISSN 1535-3702  Vol. 237  Nº 4  2012  págs. 407 - 416
Autores: Galarraga M; Campión, Francisco Javier; Boqué, Noemi; et al.
Revista: JOURNAL OF LIPID RESEARCH
ISSN 0022-2275  Vol. 53  Nº 12  2012  págs. 2791 - 2796
The accurate estimation of the number and size of cells provides relevant information on the kinetics of growth and the physiological status of a given tissue or organ. Here, we present Adiposoft, a fully automated open-source software for the analysis of white adipose tissue cellularity in histological sections. First, we describe the sequence of image analysis routines implemented by the program. Then, we evaluate our software by comparing it with other adipose tissue quantification methods, namely, with the manual analysis of cells in histological sections (used as gold standard) and with the automated analysis of cells in suspension, the most commonly used method. Our results show significant concordance between Adiposoft and the other two methods. We also demonstrate the ability of the proposed method to distinguish the cellular composition of three different rat fat depots. Moreover, we found high correlation and low disagreement between Adiposoft and the manual delineation of cells. We conclude that Adiposoft provides accurate results while considerably reducing the amount of time and effort required for the analysis.-Galarraga, M., J. Campion, A. Munoz-Barrutia, N. Boque, H. Moreno, J. A. Martinez, F. Milagro, and C. Ortiz-de-Solorzano. Adiposoft: automated software for the analysis of white adipose tissue cellularity in histological sections.
Autores: Etxeberria, Jon Ander; de la Garza, Ana Laura Isabel; Campión, Francisco Javier; et al.
Revista: Expert Opinion On Emerging Therapeutic Targets
ISSN 1472-8222  Vol. 16  Nº 3  2012  págs. 269 - 297
Autores: Cordero, Paúl; Milagro FI; Campión, Francisco Javier; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 5  Nº 4-5  2012  págs. 236 - 237
Autores: Milagro FI; Abete, Itziar; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 5  Nº Suppl. 1  2012  págs. 171
Autores: Hermsdorff HH; Milagro FI; Campión, Francisco Javier; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 5  Nº 4-5  2012  págs. 234
Autores: Abete, Itziar; Milagro FI; et al.
Revista: NUTRICION HOSPITALARIA
ISSN 0212-1611  Vol. 27  Nº 5  2012  págs. 1718
Autores: Campión, Francisco Javier; Milagro FI; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 5  Nº Suppl. 1  2012  págs. 173
Autores: de la Garza, Ana Laura Isabel; Etxeberria, Usune; Milagro FI; et al.
Revista: NUTRICION HOSPITALARIA
ISSN 0212-1611  Vol. 27  Nº 5  2012  págs. 48
Autores: de la Garza, Ana Laura Isabel; Etxeberria, U.; Campión, Francisco Javier; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 5  Nº Suppl. 1  2012  págs. 143
Autores: Varela, M.; Milagro FI; et al.
Revista: FEBS JOURNAL
ISSN 1742-464X  Vol. 279  Nº S1  2012  págs. 397 - 397
Autores: Milagro FI; Martínez, JA; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 5  Nº Suppl. 1  2012  págs. 173
Autores: Boqué, Noemi; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 4  Nº 6  2011  págs. 344 - 353
Autores: Marzo F; Milagro FI; Urdaneta E; et al.
Revista: JOURNAL OF ANIMAL PHYSIOLOGY AND ANIMAL NUTRITION
ISSN 0931-2439  Vol. 95  Nº 5  2011  págs. 591 - 598
The objective of the present study was to evaluate the influence of raw and extruded kidney bean (Phaseolus vulgaris L. var. Pinto) consumption on the gut physiology of young growing rats. The intestinal enzyme activity (sucrase, maltase, Na(+) /K(+) ATPase, aminopeptidase N, dipeptidylpeptidase IV, alkaline phosphatase) and the uptake of sugar (d-galactose) and amino acids (l-leucine) were measured in brush border membrane vesicles. Five groups of growing male Wistar rats were fed ad libitum for 15 days on five different 10% protein diets: one containing casein as the main source of protein (Control, C), and four containing raw (RKB1, RKB6) or extruded kidney bean (EKB1, EKB6) at 1% and 6% of total protein content respectively. Extrusion treatment significantly reduced the content of bioactive factors (phytates, tannins) and abolished lectins, trypsin, chymotrypsin, and ¿-amylase inhibitory activities. Rats fed raw beans (especially RKB6) showed lower growth rate and food intake as compared to those fed extruded legumes, probably due to the high levels of lectins and other anti-nutritive factors in the raw beans. Gut enzymatic activities and uptake of d-galactose and l-leucine were lower in RKB6 and RKB1-fed animals, although they significantly improved in the groups fed extruded beans. Enzymatic activity and uptake in EKB1 were similar to those of casein-fed rats, whereas the uptake and growth rate of EKB6 were different to the control. This is attributable to the higher non-thermolabile biofactor content in the EKB6 diet, especially phytates and tannins, than in EKB1. This article shows the dose-dependent toxicological effects of bioactive factors contained in kidney beans on gut function. The extrusion process reduced their adverse impact on gut physiology and growth rate.
Autores: García, Diego Fernando; Milagro FI; et al.
Revista: Physiology & Behavior
ISSN 0031-9384  Vol. 103  Nº 2  2011  págs. 173 - 180
Autores: Milagro FI; Campión, Francisco Javier; Cordero, Paúl; et al.
Revista: FASEB J
ISSN 0892-6638  Vol. 25  Nº 4  2011  págs. 1378 - 1389
Autores: García, Diego Fernando; Arellano, AV; Milagro FI; et al.
Revista: Journal of physiology and biochemistry
ISSN 1138-7548  Vol. 67  Nº 3  2011  págs. 453 - 461
Autores: de la Garza, Ana Laura Isabel; Milagro FI; Boqué, Noemi; et al.
Revista: PLANTA MED
ISSN 0032-0943  Vol. 77  Nº 8  2011  págs. 773 - 785
Autores: Gómez-Abellán, P; Gómez-Santos, C; Madrid, JA; et al.
Revista: Nutricion Hospitalaria
ISSN 0212-1611  Vol. 26  Nº 6  2011  págs. 1394 - 1401
Autores: Milagro FI; Campión, Francisco Javier; et al.
Revista: Lipids in Health and Disease
ISSN 1476-511X  Vol. 10  Nº 1  2011  págs. 55
Autores: García, Diego Fernando; Campión, Francisco Javier; et al.
Revista: Mol Nutr Food Res
ISSN 1613-4125  Vol. 55  2011  págs. 257 - 263
Autores: Cordero, Paúl; Campión, Francisco Javier; Milagro FI; et al.
Revista: Journal of physiology and biochemistry
ISSN 1138-7548  Vol. 67  Nº 3  2011  págs. 463 - 470
Autores: Cordero, Paúl; Campión, Francisco Javier; Milagro FI; et al.
Revista: Hepatology
ISSN 0270-9139  Vol. 53  Nº 6  2011  págs. 2151 - 2152
Autores: Martínez, JA; Cuervo, M; Milagro FI;
Revista: REVISTA ESPAÑOLA DE NUTRICION HUMANA Y DIETETICA
ISSN 2173-1292  Vol. 15  Nº 3  2011  págs. 124 - 125
Autores: Campión, Francisco Javier; Milagro FI; et al.
Revista: Annals of Nutrition and Metabolism
ISSN 0250-6807  Vol. 58  2011  págs. 264 - 264
Autores: de la Garza, Ana Laura Isabel; Boqué, Noemi; Campión, Francisco Javier; et al.
Revista: Annals of Nutrition and Metabolism
ISSN 0250-6807  Vol. 58  2011  págs. 20 - 21
Autores: Batle, M; Milagro FI; et al.
Revista: Annals of Nutrition and Metabolism
ISSN 0250-6807  Vol. 58  Nº 3  2011  págs. 264 - 264
Autores: García, Diego Fernando; Campión, Francisco Javier; Milagro FI; et al.
Revista: JOURNAL OF MOLECULAR ENDOCRINOLOGY
ISSN 0952-5041  Vol. 45  Nº 1  2010  págs. 33 - 43
Autores: Milagro FI; García, Diego Fernando; et al.
Revista: JOURNAL OF NUTRIGENETICS AND NUTRIGENOMICS
ISSN 1661-6499  Vol. 2  Nº 6  2010  págs. 267 - 272
Autores: Milagro FI; Campión, Francisco Javier; et al.
Revista: Biofactors
ISSN 0951-6433  Vol. 36  Nº 3  2010  págs. 159 - 168
Autores: Martínez, JA; García, Diego Fernando; et al.
Revista: Molecular Genetics and Metabolism
ISSN 1096-7192  Vol. 101  Nº 2-3  2010  págs. 273 - 278
Autores: Milagro FI; Campión, Francisco Javier; et al.
Revista: JOURNAL OF CELLULAR PHYSIOLOGY
ISSN 0021-9541  Vol. 225  Nº 1  2010  págs. 206 - 213
Autores: Cordero, Paúl; Milagro FI; Campión, Francisco Javier; et al.
Revista: Revista española de obesidad
ISSN 1696-6112  Vol. 8  Nº 1  2010  págs. 10 - 20
Autores: Campión, Francisco Javier; Milagro FI; Martínez, JA;
Revista: PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE
ISSN 1877-1173  Vol. 94  2010  págs. 291 - 347
Autores: Iffiú-Soltész, Z; Wanecq, E; et al.
Revista: Pharmacological Research
ISSN 1043-6618  Vol. 61  Nº 4  2010  págs. 355 - 363
Autores: Boqué, Noemi; Redrado M; et al.
Revista: PROSTATE
ISSN 0270-4137  Vol. 71  Nº 8  2010  págs. 824-834
Autores: Gómez-Abellán, P; Gómez-Santos, C; Madrid, JA; et al.
Revista: ENDOCRINOLOGY
ISSN 0013-7227  Vol. 151  Nº 1  2010  págs. 115 - 122
Autores: Milagro FI; Campión, Francisco Javier; et al.
Revista: Medical Hypotheses
ISSN 0306-9877  Vol. 74  Nº 5  2010  págs. 901 - 907
Autores: Milagro FI; García, Diego Fernando; et al.
Revista: Lipids in Health and Disease
ISSN 1476-511X  Vol. 9  2010  págs. 60 -
Autores: García, Diego Fernando; Arellano, A.V.; Campión, Francisco Javier; et al.
Revista: Obesity Reviews
ISSN 1467-7881  Vol. 11  2010  págs. 126
Autores: Milagro FI; et al.
Revista: Obesity Reviews
ISSN 1467-7881  Vol. 11  2010  págs. 157 - 158
Autores: Cordero, Paúl; Campión, Francisco Javier; Milagro FI; et al.
Revista: Obesity Reviews
ISSN 1467-7881  Vol. 11  2010  págs. 157
Autores: Iffiú-Soltész, Z; Valet, P; et al.
Revista: FUNDAMENTAL AND CLINICAL PHARMACOLOGY
ISSN 0767-3981  Vol. 24  Nº Supl. 1  2010  págs. 66 - 66
Autores: García, Diego Fernando; Milagro FI; et al.
Revista: Obesity Reviews
ISSN 1467-7881  Vol. 11  2010  págs. 127
Autores: Milagro FI; Martínez, JA;
Libro:  Handbook of epigenetics: the new molecular and medical genetics
2017  págs. 307 - 322
This chapter focuses on the effect of metabolic and dietary compounds, as well as the metabolic state, on relevant post-translational histone modifications, with emphasis on acetylation and methylation of histones H3 and H4. The fundamental unit of the chromatin is the nucleosome, which consists of approximately 147 base pairs of DNA wrapped around a histone octamer containing two copies of each of the four conserved core histones¿H2A, H2B, H3, and H4. Chromatin is further compacted by the incorporation of the linker histone H1, which has been reported to have eight isoforms in higher eukaryotes. There are also variant histone subspecies that are recognized by differences in their amino acid sequence relative to the major histone species. Each protein has both a histone fold domain, which mediates the histone¿histone and histone¿DNA interactions that are crucial for the assembly of the nucleosome core particle, and a flexible amino-terminal tail domain, which protrudes from the nucleosome core particle. There are various histone post-transcriptional modifications that decorate the canonical histones (H2A, H2B, H3, and H4), as well as variant histones (such as H3.1, H3.3, and HTZ.1). The combination of modifications (¿marks¿) produced by specific enzymes has been proposed to constitute a code that regulates downstream processes such as gene transcription, DNA repair, and apoptosis.
Autores: García-Lacarte, M.; Milagro FI; Martínez, JA;
Libro:  Gene-environment interactions and human diseases
2016  págs. 279 - 301
Autores: Milagro FI; Martínez, JA;
Libro:  Nutrición y salud
2015  págs. 345 - 361
En el futuro, la nutrición personalizada será una de las bases de la prevención y el tratamiento de las enfermedades. Hasta ahora se ha hecho mucho énfasis en los polimorfismos que incrementan el riesgo a sufrir alguna patología metabólica o nutricional. Sin embargo, la nutriepigenética podría ayudar a explicar los mecanismos no dependientes de la secuencia genética por los que los nutrientes y otros factores ambientales contribuyen a modular la expresión génica y el desarrollo de enfermedad. Los principales mecanismos epigenéticos son las modificaciones covalentes de las histonas, la metilación del ADN y los ARN no codificantes (como los miRNA). Estos cambios epigenéticos inducidos por factores ambientales parecen ser especialmente importantes en el período perinatal,aunque también se dan en la edad adulta. También pueden ser heredados. Entre los factores nutricionales que han sido vinculados a modificaciones epigenéticas, están los grupos donantes de metilo, la ingesta excesiva o deficiente de proteínas y calorías, algunos ácidos grasos, minerales y vitaminas, así como compuestos de origen vegetal, como polifenoles,isotiocianatos, isoflavonas y catequinas. Una de las características más interesantes de las marcas epigenéticas es que podrían ser parcialmente reversibles. Por ello, uno de los principales objetivos en este campo es el desarrollo de fármacos o la implementación de tratamientos dietéticos (por ejemplo,la «dieta epigenética») que podrían retrasar o incluso revertir estos cambios epigenéticos y, por lo tanto, evitar el desarrollo de enfermedad. El otro objetivo importante en este campo es la identificación de marcadores tempranos de enfermedad que permitan implementar tratamientos preventivos individualizados en los individuos de riesgo metabólico.
Autores: Milagro FI;
Libro:  Fundamentos de nutrición y dietética: bases metodológicas y aplicaciones
2011  págs. 119 - 122
Autores: Campión, Francisco Javier; Martínez, JA; Milagro FI;
Libro:  Genes, ciencia y dieta. Lecciones sobre evolución humana
2011  págs. 87 - 97
Autores: Milagro FI; Ansorena D;
Libro:  Fundamentos de Nutrición y Dietética: bases metodológicas y aplicaciones
2011  págs. 221 - 224
Autores: Cordero, Paúl; Milagro FI; Campión, Francisco Javier;
Libro:  Fundamentos de nutrición y dietética: bases metodológicas y aplicaciones
2011  págs. 397 - 401
Autores: Campión, Francisco Javier; Milagro FI; Martínez, JA;
Libro:  Progress in molecular biology and translational science
Vol. 94  2010  págs. 291 - 347
The etiology of obesity is multifactorial, involving complex interactions among the genetic makeup, neuroendocrine status, fetal programming, and different unhealthy environmental factors, such as sedentarism or inadequate dietary habits. Among the different mechanisms causing obesity, epigenetics, defined as the study of heritable changes in gene expression that occur without a change in the DNA sequence, has emerged as a very important determinant. Experimental evidence concerning dietary factors influencing obesity development through epigenetic mechanisms has been described. Thus, identification of those individuals who present with changes in DNA methylation profiles, certain histone modifications, or other epigenetically related processes could help to predict their susceptibility to gain or lose weight. Indeed, research concerning epigenetic mechanisms affecting weight homeostasis may play a role in the prevention of excessive fat deposition, the prediction of the most appropriate weight reduction plan, and the implementation of newer therapeutic approaches.
Autores: Milagro FI; Campión, Francisco Javier; Martínez, JA;
Libro:  Handbook of epigenetics : the new molecular and medical genetics
2010  págs. 295 - 311