Characterization of the cellular and molecular mechanisms involved in the physiopathological alterations that occur during obesity and aging and the search for nutritional, lifestyle, and therapeutic strategies to prevent or to treat them
Obesity is associated with the development of metabolic diseases such as type 2 diabetes, fatty liver and certain types of cancer. Obesity leads to a decrease in life expectancy because it favours a range of cellular processes that lead to ageing. It is well known that ageing is accompanied by an increase in visceral fat and the development of metabolic complications. Both ageing and obesity have been identified as low-grade chronic inflammatory pathologies. The inflammation associated with ageing (inflammaging) is considered a risk factor for most diseases associated with age and therefore with morbi-mortality in the elderly. However, the underlying mechanisms have not been fully identified. Our research will focus on :
1.1. Identification of the mechanisms involved in the chronic inflammation that occurs in obesity and aging “inflammaging”, including the study of the profile in specialized pro-resolving lipid mediators of inflammation.
1.2. To carry out an integrated study of the pathophysiological and metabolic changes and the altered crosstalk between key metabolic organs, including adipose tissue (white, brown, beige and bone marrow), muscle and the gastrointestinal tract (fatty liver, impaired bowel function and microbiota), as well as their correlation with changes in the length of the telomeres, and neurocognitive disorders.
1.3. Characterization of the therapeutic potential of different nutrients and bioactive molecules, such as DHA and / or its lipid mediators, as well as to identify mechanisms underlying the beneficial effects of chronic exercise training on adipose tissue and muscle function and in metabolic homeostasis.
Characterization of mechanisms involved in the activation of brown fat and in the browning of white fat and identification of therapeutic / nutritional targets as a strategy to combat obesity and associated metabolic complications (insulin resistance, type 2 diabetes and fatty liver)
Stimulating the recruitment and activity of classical brown and beige adipocytes has been proposed as a promising strategy against obesity and its deleterious associated-disorders. The current challenges include the understanding of the mechanisms underlying the loss of brown/beige activity during aging and the characterization of strategies to prevent this loss or to reactivate brown/beige depots. Our aim is to identify novel metabolic, immune and nutritional regulators of brown and beige adipose tissue activity. More specifically, we will focus on studying the role of:
2.1. Factors related to the immune system and / or the resolution of inflammation as potential agents able to regulate brown fat, and adipose tissue browning.
2.2. Factors involved in the regulation of the cell cycle (Cdks, cyclins) as modulating agents of the development, metabolism and activity of brown and beige adipocytes.
2.3. miRNAs in the regulation of white / brown / beige fat, especially in situations of obesity, hypoxia and inflammation.
Regulation of nutrient transporters in physiological and pathophysiological conditions
During intestinal inflammation tumour necrosis factor alpha (TNF-α) level is increased and malabsorption of nutrients may occur. We have previously demonstrated in Caco-2 cells that TNF-α inhibits sugar uptake by decreasing the amount of the Na+-glucose cotransporter SGLT1 in the plasma membrane. The aim of our project is to demonstrate the crosstalk between obesity and intestinal inflammation and dysfunction. Also, we aim to investigate the ability of bioactive molecules, including omega-3 fatty acids and their lipid mediators resolvins (Rv), protectins and maresins (MaR), to counteract the inhibitory effect of TNFα on sugar and amino acids transport.
On the other, our research is also focused in investigating the physiological role of the facilitative glucose transporter GLUT12 in small intestine, adipose tissue, muscle, brain and kidney, and its possible implications in obesity, aging and Alzheimer and cancer.