Study On The Metabolic Phenotypes In Adipose-specific Deletion Of Sirt6 Mice And The Molecular Mechanism Of Sirt6 In Thermogenesis

Obesity is usually a risk factor for type Ⅱ diabetes,atherosclerosis and cancer.Over the past 30 years,the incidence of obesity morbidity has increased doubly,but there is still no effective cure for it.Brown and beige fat,which can dissipate energy in the form of heat through uncoupling of respiration,are hopeful targets to combat obesity.Of the sirtuins,SIRT6 is unique in its constitutive localization to chromatin and functions as an ADP-ribosyltransferase and NAD+-dependent deacetylase of both acetyl groups and long-chain fatty-acyl groups.SIRT6 has been shown to have a leading role in regulating genomic stability,aging,glucose metabolism,stress response,life span,circadian rhythm,cardiac hypertrophy and tumorgenesis.However,its role in adipose tissue remains elusive.Here,we show that Sirt6 is enriched in BAT,and its expression is inhibited in obese animals.The expression of Sirt6 is induced by cold stress and β-agonist in both BAT and subcutaneous WAT.Deletion of SIRT6 in adipose tissue markedly impairs thermogenic function of brown adipocytes,causing a remarkable morphological"whitening" of brown fat,reduced oxygen consumption,decreased core body temperature and obesity.Moreover,fat SIRT6-deleted mice exhibit increased blood glucose levels,severe insulin resistance and hepatic steatosis.Adipose tissue-specific ablation of Sirt6 impairs energy expenditure,suppresses fatty acid oxidation and reduces thermogenesis.Consistently,mice lacking SIRT6 in adipose tissue have defects in the thermogenic response to cold exposure and β3-adrenergic receptor agonist CL316,243.Depletion of SIRT6 expression in primary brown fat cells markedly reduces expression of thermogenic genes,causing a reduction in cellular respiration.Conversely,overexpression of SIRT6 in primary fat cells stimulates thermogenic program,suggesting that the effect of SIRT6 on thermogenesis in mouse fat tissue is cell autonomous.Mechanistically,SIRT6 interacts with and promotes phospho-ATF2 binding to PGC-la gene promoter to activate its expression.SIRT6 deficiency reduces phospho-ATF2 binding to PGC-la promoter,thereby decreasing expression of PGC-la and mitochondrial genes.Our data suggest that SIRT6 is required for the maintenance of identity and function of thermogenic adipocytes.SIRT6 may be therapeutically targeted to treat obesity and type Ⅱ diabetes.