SIRT6 Regulates Metabolic Homeostasis Through Specific Functions In Skeletal Muscle And Adipose Tissue

Type 2 diabetes mellitus(T2DM)and obesity have been to be the most common metabolic diseases in the world.However,the primary cause of T2DM and obesity is still unknown,and there is still no effective clinical treatment for them.Therefore,it is the looming need to exploring the pathogenesis of T2DM and obesity,and developing better approaches for treatment.Skeletal muscle and adipose tissue play important roles on energy metabolism of the whole body,and are also critical organs regulating glucose and lipid metabolism.Sirtuin 6(SIRT6)is a NAD+-dependent deacetylase,and has been implicated in multiple metabolic processes.However,the specific functions of SIRT6 in skeletal muscle and adipose tissue are still unknown.In our study,we generated a novel muscle-specific SIRT6 knockout mice model and a novel adipose-specific SIRT6 knockout mice model to explore the specific role of SIRT6 in skeletal muscle and adipose tissue.The mutants and their controls were subjected to a series of physiological analyses.Gain-and loss-of-function experiments were also performed in C2C12 myotubes and primary adipocytes.The mice with SIRT6 deficiency in muscle displayed impaired glucose homeostasis and insulin sensitivity,attenuated whole-body energy expenditure and weakened exercise performance.Mechanistically,deletion of SIRT6 in muscle decreased expression of genes involved in glucose and lipid uptake,fatty acid oxidation and mitochondrial oxidative phosphorylation in muscle cells due to the reduced AMPK activity.Deletion of SIRT6 in adipose tissue markedly impairs thermogenic function of brown adipocytes,causing reduced oxygen consumption,obesity,decreased core body temperature and cold sensitivity.Fat SIRT6-deleted mice also exhibit increased blood glucose levels,severe insulin resistance and hepatic steatosis.Moreover,SIRT6 deficiency inhibits browning of WAT following cold exposure or β3-agonist treatment.Mechanistically,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 a physiological regulator of muscle mitochondrial function and oxidative capacity,and it is required for the maintenance of identity and function of thermogenic adipocytes.These findings indicate that SIRT6 may be therapeutically targeted to treat T2DM and obesity.