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Diabetes. 2015 May;64(5):1576-90. doi: 10.2337/db14-1180. Epub 2014 Dec 4.

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

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China.
2
Department of Chemistry and Chemical Biology Center, Jockey Club Building for Interdisciplinary Research, The University of Hong Kong, Hong Kong, China.
3
State Key Laboratory of Pharmaceutical Biotechnology and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China yuwanghk@hku.hk.

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.

PMID:
25475438
DOI:
10.2337/db14-1180
[Indexed for MEDLINE]
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