Resveratrol Ameliorates Hyperglycemic Cultured Cells and Inhibits the Rheb/mTOR Interaction

Resveratrol (RSV) is a natural polyphenol with anti-diabetic effects and has been reported to ameliorate diabetes-induced metabolic disorders through regulating activities of the mTOR signaling pathway. To delineate the effects of RSV treatment on the mTOR signaling pathway, hyperglycemic HepG2 cells were used for the following experiments. Cellular glucose uptake assays showed that high-glucose levels in the culture medium decelerate the glucose uptake of cultured cells. Co-immunoprecipitation showed that high-glucose culture promotes the interaction between mTOR and Rheb-GTP, which is the active form of Rheb. RSV treatment of the cells suppressed this interaction and accelerated the glucose uptake. Western blotting revealed that RSV down-regulated members of the mTOR signaling pathway, namely SREBP1, p70, and S6. Additionally, RSV ameliorated the metabolic disorders, including the decreased levels of AMPK, glycogen synthase, and glucose-6-phosphatase, in hyperglycemic HepG2 cells. These results indicate that RSV inhibits the Rheb/mTOR interaction and ameliorates metabolic disorders associated with high-glucose levels.