Resveratrol Promotes Gluconeogenesis by Inhibiting SESN2-mTORC2-AKT Pathway in Calf Hepatocytes

The glucose requirement of dairy cows is mainly met by increasing the rate of hepatic gluconeogenesis. However, due to negative energy balance, the liver of periparturient cows is under oxidative stress induced by lipid over-mobilization, and hepatic gluconeogenesis is reduced. Studies have demonstrated that resveratrol, which is widely known for its antioxidant properties, can alter hepatic gluconeogenesis. However, it is not clear whether resveratrol could regulate hepatic gluconeogenesis by its antioxidant properties.

This study aims to investigate the precise effect of resveratrol in hepatic gluconeogenesis, the role of resveratrol on hydrogen peroxide (H₂O₂)-induced oxidative stress in hepatocytes and the potential mechanism using primary hepatocytes.

Primary hepatocytes were isolated from 5 healthy Holstein calves (1 d old, 30 to 40 kg, fasted) and treated with different concentrations of resveratrol (0, 5, 10, 25, or 50 μM) combined with or without H₂O₂ (0, 100, or 200 μM) induction for 12 h.

Resveratrol enhanced the expression of gluconeogenic genes of calf hepatocytes in a dose-dependent manner (P < 0.05). Conversely, H₂O₂ suppressed the expression of gluconeogenic genes and induced oxidative stress (P < 0.05), which was improved by resveratrol in calf hepatocytes (P < 0.001). Furthermore, the mechanistic target of rapamycin complex 2 (mTORC2)-AKT pathway was found to negatively regulate gluconeogenesis. An AKT inhibitor was used to assess the role of the mTORC2-AKT pathway in the effects of resveratrol. The results showed resveratrol promoted hepatic gluconeogenesis by inhibiting the mTORC2-AKT pathway. Moreover, sestrin 2 (SESN2) upregulated the activity of mTORC2. We further found that resveratrol decreased SESN2 levels (P < 0.001).

This study indicated that resveratrol enhances the gluconeogenic capacity of calf hepatocytes by improving H₂O₂-induced oxidative stress and modulating the activity of the SESN2-mTORC2-AKT pathway, implying that resveratrol may be a promising target for ameliorating liver oxidative stress in transition cows.