Modulation of SIRT1 activity in adipose tissue alters systemic energy homeostasis and insulin sensitivity

Abstract

RESULTS: Adipose tissue (fat) is an important metabolic and endocrine organ. Increased adiposity contributes to metabolic complications in aging population. SIRT1 is a NAD+-dependent deacetylase mediating the effects of caloric restriction on lifespan extension. Recent evidence suggests that the anti-ageing activity of SIRT1 is attributed to its regulatory functions in energy metabolism. Activators of SIRT1 protect animals against obesity-induced metabolic damages. However, the precise mechanism whereby SIRT1 regulates energy metabolism is yet to be addressed. In the present study, adipose tissue-specific transgenic mice overexpressing SIRT1 or the dominant negative deacetylase mutant SIRT1(H363Y) are established for elucidating the physiological roles of this anti-aging protein in systemic insulin sensitivity and glucose/lipid homeostasis. The results demonstrate that selective activation of SIRT1 in adipose tissue per se improves energy homeostasis and insulin sensitivity, whereas loss-of-adipose SIRT1 function promotes aging-associated insulin resistance and glucose intolerance. Importantly, modulation of adipose SIRT1 alters biotin distribution/bioavailability and biotin-dependent enzyme activities in fat, liver and muscle. It has been known for years that the water soluble vitamin biotin acts as a prosthetic factor of four carboxylase enzymes critically involved in regulating energy metabolism. By focusing on the key lipid metabolic enzyme, acetyl CoA carboxylase, the present study demonstrates that adipose SIRT1 regulates energy metabolism and insulin sensitivity in part through regulating biotin homeostasis. Moreover, the retrograde regulation of biotin-SIRT1 axis is implicated in tissue-specific cross-talks. In summary, adipose SIRT1 represents an effective target for developing therapies against ageing and the associated metabolic abnormalities.