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Am J Transl Res 2013;5(4):412-426
Original Article
Selective overexpression of human SIRT1 in adipose tissue enhances
energy homeostasis and prevents the deterioration of insulin
sensitivity with ageing in mice
Cheng Xu, Bo Bai, Pengcheng Fan, Yu Cai, Bosheng Huang, Ivy KM Law, Ling Liu, Aimin Xu, Chunling Tung,
Xuechen Li, Fung-Ming Siu, Chi-Ming Che, Paul M Vanhoutte, Yu Wang
Department of Pharmacology and Pharmacy, Department of Chemistry and Open Laboratory of Chemical Biology
of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong
Kong, China
Received May 6, 2013; Accepted May 21, 2013; Epub May 24, 2013; Published June 1, 2013
Abstract: SIRT1, a longevity regulator and NAD+-dependent deacetylase, plays a critical role in promoting
metabolic fitness associated with calorie restriction and healthy ageing. Using a tissue-specific transgenic
approach, the present study demonstrates that over-expression of human SIRT1 selectively in adipose tissue of
mice prevents ageing-induced deterioration of insulin sensitivity and ectopic lipid distribution, reduces whole
body fat mass and enhances locomotor activity. During ageing, the water-soluble vitamin biotin is progressively
accumulated in adipose tissue. Over-expression of SIRT1 alleviates ageing-associated biotin accumulation and
reduces the amount of biotinylated proteins, including acetyl CoA carboxylase, a major reservoir of biotin in
adipose tissues. Chronic biotin supplementation increases adipose biotin contents and abolishes adipose
SIRT1-mediated beneficial effects on insulin sensitivity, lipid metabolism and locomotor activity. Biochemical,
spectrometric and chromatographic analysis revealed that biotin and its metabolites act as competitive inhibitors
of SIRT1-mediated deacetylation. In summary, these results demonstrate that adipose SIRT1 is a key player in
maintaining systemic energy homeostasis and insulin sensitivity; enhancing its activity solely in adipose tissue
can prevent ageing-associated metabolic disorders. (AJTR1305003).
Keywords: SIRT1, NAD+-dependent deacetylase, adipose tissue, biotin, longevity regulator
Address 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: yuwanghk@hku.hk
Original Article
Selective overexpression of human SIRT1 in adipose tissue enhances
energy homeostasis and prevents the deterioration of insulin
sensitivity with ageing in mice
Cheng Xu, Bo Bai, Pengcheng Fan, Yu Cai, Bosheng Huang, Ivy KM Law, Ling Liu, Aimin Xu, Chunling Tung,
Xuechen Li, Fung-Ming Siu, Chi-Ming Che, Paul M Vanhoutte, Yu Wang
Department of Pharmacology and Pharmacy, Department of Chemistry and Open Laboratory of Chemical Biology
of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Hong
Kong, China
Received May 6, 2013; Accepted May 21, 2013; Epub May 24, 2013; Published June 1, 2013
Abstract: SIRT1, a longevity regulator and NAD+-dependent deacetylase, plays a critical role in promoting
metabolic fitness associated with calorie restriction and healthy ageing. Using a tissue-specific transgenic
approach, the present study demonstrates that over-expression of human SIRT1 selectively in adipose tissue of
mice prevents ageing-induced deterioration of insulin sensitivity and ectopic lipid distribution, reduces whole
body fat mass and enhances locomotor activity. During ageing, the water-soluble vitamin biotin is progressively
accumulated in adipose tissue. Over-expression of SIRT1 alleviates ageing-associated biotin accumulation and
reduces the amount of biotinylated proteins, including acetyl CoA carboxylase, a major reservoir of biotin in
adipose tissues. Chronic biotin supplementation increases adipose biotin contents and abolishes adipose
SIRT1-mediated beneficial effects on insulin sensitivity, lipid metabolism and locomotor activity. Biochemical,
spectrometric and chromatographic analysis revealed that biotin and its metabolites act as competitive inhibitors
of SIRT1-mediated deacetylation. In summary, these results demonstrate that adipose SIRT1 is a key player in
maintaining systemic energy homeostasis and insulin sensitivity; enhancing its activity solely in adipose tissue
can prevent ageing-associated metabolic disorders. (AJTR1305003).
Keywords: SIRT1, NAD+-dependent deacetylase, adipose tissue, biotin, longevity regulator
Address 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: yuwanghk@hku.hk
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