Selective overexpression of human SIRT1 in adipose tissue enhances energy homeostasis and prevents the deterioration of insulin sensitivity with ageing in mice

Abstract

SIRT1, a longevity regulator and NAD+-dependent deacetylase, plays a critical role in promoting metabolic fitness associated with calorie restriction and healthy ageing. Using a tissue-specific transgenic approach, the present study demonstrates that over-expression of human SIRT1 selectively in adipose tissue of mice prevents ageinginduced deterioration of insulin sensitivity and ectopic lipid distribution, reduces whole body fat mass and enhances locomotor activity. During ageing, the water-soluble vitamin biotin is progressively accumulated in adipose tissue. Over-expression of SIRT1 alleviates ageing-associated biotin accumulation and reduces the amount of biotinylated proteins, including acetyl CoA carboxylase, a major reservoir of biotin in adipose tissues. Chronic biotin supplementation increases adipose biotin contents and abolishes adipose SIRT1-mediated beneficial effects on insulin sensitivity, lipid metabolism and locomotor activity. Biochemical, spectrometric and chromatographic analysis revealed that biotin and its metabolites act as competitive inhibitors of SIRT1-mediated deacetylation. In summary, these results demonstrate that adipose SIRT1 is a key player in maintaining systemic energy homeostasis and insulin sensitivity; enhancing its activity solely in adipose tissue can prevent ageing-associated metabolic disorders.