Abstract
Mammalian sirtuin 6 (SIRT6) is involved in the regulation of many essential processes, especially metabolic homeostasis. SIRT6 knockout mice undergo premature aging and die at age ~4 weeks. Severe glycometabolic disorders have been found in SIRT6 knockout mice, and whether a dietary intervention can rescue SIRT6 knockout mice remains unknown. In our study, we found that at the same calorie intake, a high‐fat diet dramatically increased the lifespan of SIRT6 knockout mice to 26 weeks (males) and 37 weeks (females), reversed multi‐organ atrophy, and reduced body weight, hypoglycemia, and premature aging. Furthermore, the high‐fat diet partially but significantly normalized the global gene expression profile in SIRT6 knockout mice. Regarding the mechanism, excessive glucose uptake and glycolysis induced by the SIRT6 deficiency were attenuated in skeletal muscle through inhibition of insulin and IGF1 signaling by the high‐fat diet. Similarly, fatty acids but not ketone bodies inhibited glucose uptake, glycolysis, and senescence in SIRT6 knockout fibroblasts, whereas PI3K inhibition antagonized the effects of a high‐fatty‐acid medium in vitro. Overall, the high‐fat diet dramatically reverses numerous consequences of SIRT6 deficiency through modulation of insulin and IGF1 signaling, providing a new basis for elucidation of SIRT6 and fatty‐acid functions and supporting novel therapeutic approaches against metabolic disorders and aging‐related diseases.
Highlights
Alterations in glycometabolism have been proposed to underlie the diverse aberrations associated with sirtuin 6 (SIRT6) deficiency (Zhong et al, 2010), and many aging-related diseases derive from chronic metabolic problems in our daily life
As for the mechanism, we show that overactivation of insulin and IGF1–PI3K signaling caused by the SIRT6 deficiency is dramatically attenuated by the highfat diet
There were no remarkable differences in total cholesterol (CHO) between WT and KO mice, but the high-density lipoprotein cholesterol/ CHO ratio decreased while the low-density lipoprotein cholesterol/CHO ratio increased as a result of the SIRT6 deficiency; these changes were significantly attenuated by the high-fat diet only in male mice (Figure S1)
Summary
As a highly conserved family of NAD+-dependent deacetylases, are a class of molecules exerting broad influence on numerous biological pathways (Finkel, Deng, & Mostoslavsky, 2009). There were no remarkable differences in total cholesterol (CHO) between WT and KO mice, but the high-density lipoprotein cholesterol/ CHO ratio decreased while the low-density lipoprotein cholesterol/CHO ratio increased as a result of the SIRT6 deficiency; these changes were significantly attenuated by the high-fat diet only in male mice (Figure S1) These results suggested that the high-fat diet but not the glucose supplement extended the lifespan and reversed the low body weight of SIRT6 KO mice. We did find increased lactic acid levels in the blood and muscle tissue of SIRT6 KO mice, and the high-fat diet effectively decreased these lactic acid concentrations (Figure 5c). As the key regulators of glucose metabolism and lipogenesis, insulin and IGF1 signaling cascades were affected by the SIRT6 KO and by the high-fat diet The latter increased the serum insulin concentration in the SIRT6 KO mice, but had no effect on the IGF1 level (Figure 5d). These results indicated that the influence of fatty acids on SIRT6 KO-induced excessive glycolysis in MEFs was PI3K dependent (Figure 7c)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
