Regulation of PPARγ activity during adipogenesis
Regulation of PPARγ activity during adipogenesis
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DOI：
10.1038/sj.ijo.0802907
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发表时间：
2005-03-01
影响因子：
4.9
通讯作者：
Farmer, SR
中科院分区：
文献类型：
--
作者：
Farmer, SR
过氧化物酶体增殖物激活受体γ(PPARGamma)是一种核受体，在多种细胞类型中调节一系列不同的功能，包括调节与生长和分化相关的基因。它最显著的功能是调节脂肪组织的发育，这涉及协调数百个基因的表达，这些基因负责建立成熟的脂肪细胞表型。我们最近的研究表明，MEK/ERK信号和CCAAT/增强子结合蛋白(C/EBP)β在脂肪形成过程中调节PPARGamma的表达。此外，我们还证明了cAMP依赖的信号与C/EBPβ一起通过可能涉及产生PPARγ配体的机制来刺激PPARγ的活性。此外，我们最近已经证明，在脂肪形成的终末阶段，脂联素的PPARγ相关表达需要在一致的ERK/GSK3位点上C/EBPB的磷酸化。GSK3β还通过调节Wnt信号的有效转录激活剂β-catenin的周转和亚细胞定位来影响PPAR-Gamma的活性。事实上，我们最近展示了PPAR-Gamma和β-catenin信号之间的串扰。具体地说，PPARGamma的激活通过需要GSK3β和蛋白酶体的机制诱导前脂肪细胞分化过程中β-连环素的降解。相反，GSK3β-磷酸化缺陷的β-连环蛋白的表达使β-连环蛋白对PPARGamma的降解作用具有抵抗力。有趣的是，突变的β-连环蛋白的表达阻止了脂联素和C/EBPalpha的表达，以响应PPARγ的激活。
Peroxisome proliferator-activated receptor gamma (PPARgamma) 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)beta in regulating expression of PPARgamma during adipogenesis. Furthermore, we have shown that cAMP-dependent signaling along with C/EBPbeta leads to the stimulation of PPARgamma activity by mechanisms that probably involve production of PPARgamma ligands. Additionally, we have recently demonstrated that phosphorylation of C/EBPb at a consensus ERK/GSK3 site is required for the PPARgamma-associated expression of adiponectin during the terminal stages of adipogenesis. GSK3beta also influences PPARgamma activity by regulating the turnover and subcellular localization of beta-catenin, a potent transcriptional activator of Wnt signaling. In fact, we have recently shown a crosstalk between PPARgamma and beta-catenin signaling. Specifically, activation of PPARgamma induces the degradation of beta-catenin during preadipocyte differentiation by mechanisms that require GSK3beta and the proteasome. In contrast, expression of a GSK3beta-phosphorylation-defective beta-catenin renders beta-catenin resistant to the degradatory action of PPARgamma. Interestingly, expression of the mutant beta-catenin blocks expression of adiponectin and C/EBPalpha in response to the activation of PPARgamma.