Biochem J 2006 Apr 21; (Read article online)

Zhang J

Resveratrol mimics calorie restriction to extend lifespan of C. elegans, yeast and Drosophila, possibly through activation of Sir2, a NAD-dependent histone deacetylase. In this study, resveratrol is shown to inhibit insulin signaling pathway in several cell lines and rat primary hepatocytes in addition to its broad spectrum inhibitions of several signaling pathways. Resveratrol effectively inhibits insulin-induced AKT and MAPK activation mainly through disruption of the interactions between insulin receptor substrates and its downstream binding proteins including p85 regulatory subunit of PI-3 kinase and Grb2. The inhibitory effect of resveratrol on insulin signaling is also demonstrated at mRNA level, where resveratrol reverses insulin effects on Phosphoenoylpyruvate carboxykinase (PEPCK), Glucose-6-Phosphatase (G-6-Pase), Fatty acid synthase (FAS) and Glucokinase (GK). In addition, RNAi experiment shows that the inhibitory effect of resveratrol on insulin signaling pathway is not weakened in cells with reduced expression of SirT1, the mammalian counterpart of Sir2. These observations raise the possibility that resveratrol may additionally modulate lifespan through inhibition of insulin signaling pathway, independently of its activation of SirT1 histone deacetylase. Furthermore, this study may help explain a wide range of biological effects of resveratrol, and provides further insight into the molecular basis of calorie restriction.