Modulation of peroxisome proliferator-activated receptor gamma stability and transcriptional activity in adipocytes by resveratrol.

The peroxisome proliferator-activated receptor (PPAR) gamma is essential for the formation and function of adipocytes. It is also involved in regulating insulin sensitivity and is the functional target of the thiazolidinedione class of insulin-sensitizing drugs. Whereas thiazolidinediones activate PPARgamma and decrease PPARgamma protein levels, genetic models indicate that decreased expression of PPARgamma is also associated with increased insulin sensitivity. In this study, we show that resveratrol modulates PPARgamma protein levels in 3T3-L1 adipocytes via inhibition of PPARgamma gene expression coupled with increased ubiquitin-proteasome-dependent degradation of PPARgamma proteins. Resveratrol-mediated decreases in PPARgamma expression are associated with repression of PPARgamma transcriptional activity when assayed using a panel of PPARgamma target genes in adipocytes. Finally, we demonstrate that resveratrol inhibits insulin-dependent changes in glucose uptake and glycogen levels and decreases insulin receptor substrate 1 and glucose transporter 4 protein levels, indicating that resveratrol represses insulin sensitivity in adipocytes. These results indicate that the resveratrol-mediated effects in adipocytes involve regulation of PPARgamma expression and transcriptional activity along with decreased responsiveness to insulin.