Page 1 of 205 Diabetes Calorie restriction prevents metabolic ageing caused by abnormal SIRT1 function in adipose tissues Cheng Xu1, Yu Cai1, Pengcheng Fan1, Bo Bai1, Jie Chen1, Han-Bing Deng1, Chi-Ming Che2, Aimin Xu1, Paul M Vanhoutte1, Yu Wang*,1 1State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, and 2Department of Chemistry and Chemical Biology Center, Jockey Club Building for Interdisciplinary Research, The University of Hong Kong, Hong Kong, China. *Correspondence to: Dr Yu Wang, Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China, Tel: (852) 28192864; Fax (852) 28170859; E- mail:
[email protected] Running Title: SIRT1, histone biotinylation and metabolic ageing 1 Diabetes Publish Ahead of Print, published online December 4, 2014 Diabetes Page 2 of 205 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.