title: Selective overexpression of human SIRT1 in adipose tissue enhances energy homeostasis and prevents the deterioration of insulin sensitivity with ageing in mice.
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.
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong Hong Kong, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Xu
authors.forename: Bo
authors.initials: B
authors.lastname: Bai
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Fan
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.forename: Bosheng
authors.initials: B
authors.lastname: Huang
authors.forename: Ivy Km
authors.initials: IK
authors.lastname: Law
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Chunling
authors.initials: C
authors.lastname: Tung
authors.forename: Xuechen
authors.initials: X
authors.lastname: Li
authors.forename: Fung-Ming
authors.initials: FM
authors.lastname: Siu
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
authors.forename: Paul M
authors.initials: PM
authors.lastname: Vanhoutte
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
keywords: NAD+-dependent deacetylase; SIRT1; adipose tissue; biotin; longevity regulator