Role of adipose SIRT1 in regulating systemic energy metabolism

SIRT1 (sirtuin 1), a mammalian ortholog of the longevity regulator yeast Sir2p, elicits diversified functions by mediating NAD+ -dependent deacetylation of protein targets. SIRT1 contributes to the beneficial effects of calorie restriction, the non-genetic intervention capable of promoting longevity and reducing the incidence of age-related disorders. In mammals, SIRT1 acts as a metabolic regulator in response to environmental stress signals. Activation of SIRT1 protects mice against diet-induced obesity and insulin resistance. However, the tissue specific metabolic functions of SIRT1 remain to be defined. The present study shows that over-expression of human SIRT1 selectively in adipose tissue decreases circulating lipid levels, reduces whole body fat mass, and elevates systemic insulin sensitivity. By contrast, over-expression of a dominant-negative human SIRT1 mutant H363Y in adipose tissue accelerates the development of aging-associated insulin resistance. Activation or down-regulation of adipose SIRT1 promotes lipid mobilization towards different metabolic organs and alters biotin homeostasis in opposite manners. Adipose SIRT1 positively regulates lipid metabolism, genes expression and adipokines secretion which are negatively influenced by SIRT1 H363Y mutant. Biotin is a water soluble vitamin and plays an important role in energy metabolism. The present study shows that biotin and its metabolites are the endogenous inhibitors of SIRT1 enzymatic activity. Chronic biotin supplementation abolishes adipose SIRT1-mediated beneficial effects on lipid metabolism. These effects are partly explained by the regulation of acetyl-CoA carboxylase (ACC), a key regulator of lipid metabolism and biotin homeostasis. SIRT1 selectively deacetylates and negatively regulate the protein stability of ACC. Over-expression of SIRT1 in fat cells persistently down-regulates ACC expression. The direct interaction between SIRT1 and ACC are subjected to rapid regulation by nutrient status which can explain the beneficial effect of SIRT1 in energy homeostasis. In mice subjected to chronic treatment with biotin, the interactions between SIRT1 and ACC were significantly inhibited. Taken in conjunction, the above findings reveal that SIRT1 in adipose tissue functions to regulate systemic energy metabolism and insulin sensitivity. In particular, it plays a critical role in modulating ACC protein levels and biotin homeostasis in adipose tissue, which in turn facilitate lipid storage and utilization in response to nutrient level changes.published_or_final_versionPharmacology and PharmacyDoctoralDoctor of Philosoph