Modulation of peroxisome proliferator-activated receptor γ 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 PPAR gamma and decrease PPAR gamma protein levels, genetic models indicate that decreased expression of PPAR gamma is also associated with increased insulin sensitivity. In this study, we show that resveratrol modulates PPAR gamma protein levels in 3T3-L1 adipocytes via inhibition of PPAR gamma gene expression coupled with increased ubiquitin-proteasome-dependent degradation of PPAR gamma proteins. Resveratrol-mediated decreases in PPAR gamma expression are associated with repression of PPAR gamma transcriptional activity when assayed using a panel of PPAR gamma 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 PPAR gamma expression and transcriptional activity along with decreased responsiveness to insulin. (C) 2008 Elsevier Inc. All rights reserved.