Modulation of peroxisome proliferator–activated receptor γ stability and transcriptional activity in adipocytes by resveratrol

The peroxisome proliferator–activated receptor (PPAR) γ 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 PPARγ and decrease PPARγ protein levels, genetic models indicate that decreased expression of PPARγ is also associated with increased insulin sensitivity. In this study, we show that resveratrol modulates PPARγ protein levels in 3T3-L1 adipocytes via inhibition of PPARγ gene expression coupled with increased ubiquitin-proteasome–dependent degradation of PPARγ proteins. Resveratrol-mediated decreases in PPARγ expression are associated with repression of PPARγ transcriptional activity when assayed using a panel of PPARγ 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 PPARγ expression and transcriptional activity along with decreased responsiveness to insulin.