Akt2 deficiency alleviates oxidative stress in the heart and liver via up-regulating SIRT6 during high-fat diet-induced obesity

The present study aims to investigate the role of AKT2 in the pathogenesis of hepatic and cardiac lipotoxicity induced by lipid overload-induced obesity and identify its downstream targets. WT and Akt2 KO mice were fed either normal diet, or high-fat diet (HFD) to in-duce obesity model in vivo. Human hepatic cell line (L02 cells) and neonatal rat cardiomy-ocytes (NRCMs) were used as in vitro models. We observed that during HFD-induced obe-sity, Akt2 loss-of-function mitigated lipid accumulation and oxidative stress in the liver and heart tissue. Mechanistically, down-regulation of Akt2 promotes SIRT6 expression in L02 cells and NRCMs, the latter deacetylates SOD2, which promotes SOD2 activity and there-fore alleviates oxidative stress-induced injury of hepatocytes and cardiomyocytes. Further-more, we also proved that AKT2 inhibitor protects hepatocytes and cardiomyocytes from HFD-induced oxidative stress. Therefore, our work prove that AKT2 plays an important role 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.