Abstract

Objective: Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5′-AMP activated kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPKα1 or α2 to determine if the metabolic effects of resveratrol are mediated by AMPK.

Research design and methods: Mice deficient in the catalytic subunit of AMPK (α1 or α2) and wild type mice were fed high-fat diet or high-fat supplemented with resveratrol for 13 weeks. Body weight was recorded by weekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts (mefs) deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro.

Results: Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPKα1−/− mice. In the absence of either AMPKα1 or α2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD/NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly.

Conclusion: We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol.