Regulation of PPARγ activity during adipogenesis

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor regulating an array of diverse functions in a variety of cell types including regulation of genes associated with growth and differentiation. Its most notable function is to regulate development of adipose tissue, which involves coordinating expression of many hundreds of genes responsible for establishment of the mature adipocyte phenotype. Our recent studies have demonstrated a role for MEK/ERK signaling and CCAAT/enhancer binding proteins (C/EBP)β in regulating expression of PPARγ during adipogenesis. Furthermore, we have shown that cAMP-dependent signaling along with C/EBPβ leads to the stimulation of PPARγ activity by mechanisms that probably involve production of PPARγ ligands. Additionally, we have recently demonstrated that phosphorylation of C/EBPβ at a consensus ERK/GSK3 site is required for the PPARγ-associated expression of adiponectin during the terminal stages of adipogenesis. GSK3β also influences PPARγ activity by regulating the turnover and subcellular localization of β-catenin, a potent transcriptional activator of Wnt signaling. In fact, we have recently shown a crosstalk between PPARγ and β-catenin signaling. Specifically, activation of PPARγ induces the degradation of β-catenin during preadipocyte differentiation by mechanisms that require GSK3β and the proteasome. In contrast, expression of a GSK3β-phosphorylation-defective β-catenin renders β-catenin resistant to the degradatory action of PPARγ. Interestingly, expression of the mutant β-catenin blocks expression of adiponectin and C/EBPα in response to the activation of PPARγ.