Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα gene expression during the differentiation of 3T3-L1 preadipocytes
Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor γ (PPARγ) and C/EBPα gene expression during the differentiation of 3T3-L1 preadipocytes
复制标题
DOI：
10.1074/jbc.m207776200
复制
发表时间：
2002-11-29
影响因子：
4.8
通讯作者：
Farmer, SR
中科院分区：
文献类型：
--
作者：
Prusty, D;Park, BH;Farmer, SR
我们证明，融合后的3T3-L1前脂肪细胞暴露于胰岛素、异丁基甲基黄嘌呤(MIX)、地塞米松(DEX)和胎牛血清中，可以诱导MEK1的快速但短暂的激活，这一点在脂肪形成的最初2小时内表现为ERK1和ERK2的广泛磷酸化。在诱导分化前用MEK1特异性抑制剂(U0126或PD98059)抑制这种活性，可显著减弱过氧化体增殖物激活受体(PPAR)γ、CCAAT/增强子结合蛋白(C/EBP)α、Perilipin和脂肪细胞特异性脂肪酸结合蛋白(AP2)的表达。用有效的PPAR-γ配体曲格列酮处理前脂肪细胞，可以绕过U0126对成脂基因表达的抑制。成纤维细胞生长因子-2在地塞米松、异丁基甲基黄嘌呤和胰岛素存在的情况下，可诱导MEK/ERK信号通路的长时间激活，这种激活至少持续12h，并且这种活性对MEK抑制剂不那么敏感。因此，U0126在成纤维细胞生长因子-2存在的情况下处理的前脂肪细胞在诱导后表达正常水平的MEK活性，并且在这样做的过程中，能够进行脂肪生成。我们进一步表明，在分化过程的早期阶段，MEK1的激活显著增强了C/EBPalpha最小启动子的反式激活。我们的结果表明，MEK/ERK信号通路在脂肪形成的最初12小时内的激活增强了调节C/EBPalpha和PPARGamma表达的因子的活性。
We demonstrate that exposure of post-confluent 3T3-L1 preadipocytes to insulin, isobutylmethylxanthine (MIX), dexamethasone (DEX), and fetal bovine serum induces a rapid but transient activation of MEK1 as indicated by extensive phosphorylation of ERK1 and ERK2 during the initial 2 h of adipogenesis. Inhibition of this activity by treating the cells with a MEK1-specific inhibitor (U0126 or PD98059) prior to the induction of differentiation significantly attenuated the expression of peroxisome proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, perilipin, and adipocyte-specific fatty acid-binding protein (aP2). Treating the preadipocytes with troglitazone, a potent PPAR-gamma ligand, could circumvent the inhibition of adipogenic gene expression by U0126. Fibroblast growth factor-2 (FGF-2), in the presence of dexamethasone, isobutylmethylxanthine, and insulin, induces a prolonged activation of the MEK/ERK signaling pathway, which lasts for at least 12 h post-induction, and this activity is less sensitive to the MEK inhibitors. Consequently, preadipocytes treated with U0126 in the presence of fibroblast growth factor-2 (FGF-2) express normal post-induction levels of MEK activity, and, in so doing, are capable of undergoing adipogenesis. We further show that activation of MEK1 significantly enhances the transactivation of the C/EBPalpha minimal promoter during the early phase of the differentiation process. Our results suggest that activation of the MEK/ERK signaling pathway during the initial 12 h of adipogenesis enhances the activity of factors that regulate both C/EBPalpha and PPARgamma expression.