Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents.

Abstract Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat–fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate–1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and I κ B α protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate–activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status.