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

Abstract

The peroxisome proliferator activated receptor gamma (PPARγ) is essential for the formation and function of adipocytes. PPARγ is also involved in regulating insulin sensitivity and is the functional target of the thiazolidinedione (TZDs) class of insulin sensitizing drugs. While TZDs activate PPARγ and decrease PPARγ protein levels, genetic models indicate 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 IRS-1 and GLUT4 protein levels, indicating resveratrol represses insulin sensitivity in adipocytes. These results indicate resveratrol-mediated effects in adipocytes involve regulation of PPARγ expression and transcriptional activity along with decreased responsiveness to insulin.

Caffeic Acid Phenethyl Ester Suppresses the Production of Adipocytokines, Leptin, Tumor Necrosis Factor -Alpha and Resistin, during Differentiation to Adipocytes in 3T3-L1 Cells

“…Resveratrol is known to have a preventive effect against adipocytes differentiation via PPARgamma expression in 3T3-L1 cells. 12) Resveratrol is also a potent activator of silencing information regulator 1 (SIRT1). 27) SIRT1 is also reported to inhibit the formation of adipocytes and to repress PPARgamma transcriptional activity.…”

The inhibitory effect of resveratrol on leptin secretion from rat adipocytes

“…As glucose catabolism enhances ATP synthesis in adipocytes, resveratrolinduced attenuation of leptin secretion may result from disturbances in glucose transport and ⁄ or metabolism. Data from the literature concerning the effects of resveratrol on glucose transport are sometimes conflicting depending on experimental conditions [41][42][43][44][45]. While in muscle cells resveratrol is reported to be a stimulator of glucose transport [41,44], in 3T3-L1 adipocytes, resveratrol was found to decrease GLUT4 protein levels and glucose uptake [45].…”

Oleuropein as an inhibitor of peroxisome proliferator-activated receptor gamma

“…Many experiments with the polyphenols demonstrated substantial modulation of physiological and molecular pathway involved in energy metabolism and adiposity (reviewed in (Meydani and Hasan 2010)). Catechins from green tea (Lin et al 2005), resveratrol from red grapes (Floyd et al 2008) and curcumin from curcuma (Ejaz et al 2009) suppressed adipogenesis on 3T3-L1 cell line through several mechanisms including attenuation of peroxisome proliferator-activated receptor c (PPARc) regulatory pathway (Manach et al 2004). Also, the olive tree, botanically known as Olea europaea, and its products are a source of at least 30 phenolic compounds, and particularly, extra-virgin olive oil contains considerable amounts of phenolic compounds, e.g., oleuropein and its hydrolysis product hydroxytyrosol, which are responsible for its peculiar taste and high stability.…”