title: 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 antiaging activities in a wide range of organisms. The current 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 aging. 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 aging-associated metabolic disorders.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Bai
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Han-Bing
authors.initials: HB
authors.lastname: Deng
authors.affiliation: Department of Chemistry and Chemical Biology Center, Jockey Club Building for Interdisciplinary Research, The University of Hong Kong, Hong Kong, China.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China yuwanghk@hku.hk.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000375:Aging / Q000502:physiology*; D000818:Animals; D019921:Biotinylation; D031204:Caloric Restriction; D042002:Chromatin Assembly and Disassembly / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006657:Histones; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D012313:RNA; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase