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 ageing-induced 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.