Chemerin, a Novel Peroxisome Proliferator-activated Receptor γ (PPARγ) Target Gene That Promotes Mesenchymal Stem Cell Adipogenesis
Chemerin, a Novel Peroxisome Proliferator-activated Receptor γ (PPARγ) Target Gene That Promotes Mesenchymal Stem Cell Adipogenesis
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DOI：
10.1074/jbc.m111.220491
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发表时间：
2011-07-08
影响因子：
4.8
通讯作者：
Sinal, Christopher J.
中科院分区：
文献类型：
--
作者：
Muruganandan, Shanmugam;Parlee, Sebastian D.;Sinal, Christopher J.
Chemerin是一种脂肪细胞分泌的蛋白质，通过激活趋化因子样受体1（CMKLR 1）调节脂肪形成和成熟脂肪细胞的代谢功能。在这里，我们报告的相互作用的过氧化物酶体增殖物激活受体γ（过氧化物酶体增殖物激活受体γ）和chemerin的背景下，脂肪形成。敲低chemerin或CMKLR 1表达或抗体中和分泌的chemerin蛋白通过诱导G（2）/M细胞周期蛋白（细胞周期蛋白A2/B2）而不是G（1）/S细胞周期蛋白D2的损失来阻止骨髓间充质干细胞（BMSCs）的成脂克隆扩增。在趋化蛋白或CMKLR 1敲低后，在BMSC中强制表达PPAR γ并不能完全挽救克隆扩增和脂肪形成的损失。然而，在BMSC以及非脂肪形成细胞类型如NIH-3 T3胚胎成纤维细胞和MCA 38结肠癌细胞中，PPAR γ的强制表达和/或活化显著诱导趋化蛋白表达和分泌。序列分析显示，一个假定的过氧化物酶体增殖物激活受体γ反应元件（PPRE）序列内的chemerin启动子。该PPRE能够赋予异源启动子对PPAR γ的响应性，并且该序列的突变消除了由PPAR γ对趋化蛋白启动子的激活。染色质免疫沉淀证实了直接协会的过氧化物酶体增殖物激活受体γ与此PPRE。用罗格列酮治疗的小鼠脂肪组织和骨髓中chemerin mRNA水平升高，与循环chemerin水平升高一致。总之，这些发现支持chemerin/CMKLR 1信号传导在脂肪细胞分化过程中克隆扩增中的基本作用，以及PPAR γ在调节chemerin表达中的作用。
Chemerin is an adipocyte-secreted protein that regulates adipogenesis and the metabolic function of mature adipocytes via activation of chemokine-like receptor 1 (CMKLR1). Herein we report the interaction of peroxisome proliferator-activated receptor gamma (PPAR gamma) and chemerin in the context of adipogenesis. Knockdown of chemerin or CMKLR1 expression or antibody neutralization of secreted chemerin protein arrested adipogenic clonal expansion of bone marrow mesenchymal stem cells (BMSCs) by inducing a loss of G(2)/M cyclins (cyclin A2/B2) but not the G(1)/S cyclin D2. Forced expression of PPAR gamma in BMSCs did not completely rescue this loss of clonal expansion and adipogenesis following chemerin or CMKLR1 knockdown. However, forced expression and/or activation of PPAR gamma in BMSCs as well as non-adipogenic cell types such as NIH-3T3 embryonic fibroblasts and MCA38 colon carcinoma cells significantly induced chemerin expression and secretion. Sequence analysis revealed a putative PPAR gamma response element (PPRE) sequence within the chemerin promoter. This PPRE was able to confer PPAR gamma responsiveness on a heterologous promoter, and mutation of this sequence abolished activation of the chemerin promoter by PPAR gamma. Chromatin immunoprecipitation confirmed the direct association of PPAR gamma with this PPRE. Treatment of mice with rosiglitazone elevated chemerin mRNA levels in adipose tissue and bone marrow coincident with an increase in circulating chemerin levels. Together, these findings support a fundamental role for chemerin/CMKLR1 signaling in clonal expansion during adipocyte differentiation as well as a role for PPAR gamma in regulating chemerin expression.