Akt2 deficiency alleviates oxidative stress in the heart and liver during high fat diet-induced obesity

Abstract

Abstract The AKT family plays key roles in global metabolism. However, the function of different AKT isoforms during obesity-associated hepatic and cardiac injury remained unclear. This study aims to elucidate the role of AKT2 in the pathogenesis of hepatic and cardiac lipotoxicity due to nutrition overload-induced obesity and explore the signaling pathway that it involves. Akt2 KO mice were fed with high fat diet (HFD) to induce obesity model in vivo. The oxidative stress of the normal human hepatic cell line (L02 cells) and neonatal rat cardiomyocytes (NRCMs) were measured by using Oil Red O and Rho123 staining as well as Flow cytometry. Protein levels were determined by using western blot technique. We observed that during HFD-induced obesity, Akt2 loss-of-function mitigated lipid accumulation and oxidative stress in the liver and heart tissue. Mechanistically, during HFD-induced obesity, Akt2 deficiency promotes SIRT6 expression in the hepatocytes and cardiomyocytes. Upregulation of SIRT6 deacetylates SOD2, which promotes SOD2 activity and thus alleviating oxidative stress-induced injury of hepatocytes and cardiomyocytes. Furthermore, We also proved that AKT2 inhibitor protects hepatocytes and cardiomyocytes from HFD-induced oxidative stress. This study demonstrates that Akt2 deficiency plays a beneficial role in protecting hepatocytes and cardiomyocytes from oxidative stress via SIRT6-dependent SOD2 deacetylation during lipid overload-induced obesity, indicating an important function of AKT2 in the regulation of obesity-induced lipid metabolic disorder in the liver and heart. Our study also indicates AKT2 inhibitor as a potential therapy for obesity-induced hepatic and cardiac injury.