Calorie Restriction Prevents Metabolic Aging Caused by Abnormal SIRT1 Function in Adipose Tissues

Abstract

Adipose tissue is a pivotal organ determining longevity, due largely to its role in maintaining whole body energy homeostasis and insulin sensitivity. SIRT1 is a NAD-dependent protein deacetylase possessing anti-ageing activities in a wide range of organisms. The present study demonstrates that mice with adipose tissue-selective overexpression of hSIRT1(H363Y), a dominant negative mutant that disrupts endogenous SIRT1 activity, show accelerated development of metabolic ageing. These mice, referred to as Adipo-H363Y, exhibit hyperglycemia, dyslipidemia, ectopic lipid deposition, insulin resistance and glucose intolerance at a much younger age than their wild type littermates. The metabolic defects of Adipo-H363Y are associated with abnormal epigenetic modifications and chromatin remodeling in their adipose tissues, as a result of excess accumulation of biotin, which inhibits endogenous SIRT1 activity, leading to increased inflammation, cellularity and collagen deposition. The enzyme acetyl-CoA carboxylase 2 plays an important role in biotin accumulation within adipose tissues of Adipo-H363Y. Calorie restriction prevents biotin accumulation, abolishes abnormal histone biotinylation, and completely restores the metabolic and adipose functions of Adipo-H363Y. The effects are mimicked by short-term restriction of biotin intake, an approach potentially translatable to humans for maintaining the epigenetic and chromatin remodeling capacity of adipose tissues and preventing ageing-associated metabolic disorders.