The Transcription Factor Paired-Related Homeobox 1 (Prrx1) Inhibits Adipogenesis by Activating Transforming Growth Factor-β (TGFβ) Signaling
The Transcription Factor Paired-Related Homeobox 1 (Prrx1) Inhibits Adipogenesis by Activating Transforming Growth Factor-β (TGFβ) Signaling
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DOI：
10.1074/jbc.m112.440370
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
MacDougald, Ormond A.
中科院分区：
文献类型：
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作者：
Du, Baowen;Cawthorn, William P.;MacDougald, Ormond A.
脂肪细胞从前脂肪细胞分化有助于肥胖症中脂肪组织的扩张。脂肪生成受损可能是代谢性疾病如胰岛素抵抗和2型糖尿病发展的基础。从机制上讲，明确定义的转录网络协调脂肪细胞分化。配对相关的同源框转录因子家族，包括Prrx 1a，Prrx 1b和Prrx 2，与间充质细胞命运的调节有关，包括肌生成和骨骼生成;然而，这些蛋白质是否影响脂肪生成仍有待解决。在这项研究中，我们确定Prrx 1a和Prrx 1b作为脂肪形成的负调节因子。我们发现，Prrx 1a和Prrx 1b在体外和体内脂肪形成过程中下调。稳定敲除Prrx 1 a/B可增强脂肪生成，增加过氧化物酶体增殖物激活受体-γ、CCAAT/增强子结合蛋白-α和FABP 4的表达，并增加脂肪因子脂联素和趋化蛋白的分泌。尽管Prrx 1a、Prrx 1b或Prrx 2的稳定低水平表达不会影响3 T3-L1脂肪生成，但Prrx 1a或Prrx 1b的短暂过表达会抑制过氧化物酶体增殖物激活受体γ活性。Prrx 1敲低降低Tgfb 2和Tgfb 3的表达，并且在脂肪形成期间抑制TGF β信号传导模拟Prrx 1敲低的作用。这些数据支持内源性Prrx 1通过调节TGF β配体的表达从而激活TGF β信号传导来抑制脂肪形成的假设。最后，我们发现在肥胖期间脂肪组织中Prrx 1a或Prrx 1b的表达增加，并且与BL 6小鼠中Tgfb 3的表达强烈相关。这些观察结果表明，Prrx 1表达增加可能会促进脂肪组织中的TGF β活性，从而导致肥胖期间脂肪细胞功能异常。
Differentiation of adipocytes from preadipocytes contributes to adipose tissue expansion in obesity. Impaired adipogenesis may underlie the development of metabolic diseases such as insulin resistance and type 2 diabetes. Mechanistically, a well defined transcriptional network coordinates adipocyte differentiation. The family of paired-related homeobox transcription factors, which includes Prrx1a, Prrx1b, and Prrx2, is implicated with regulation of mesenchymal cell fate, including myogenesis and skeletogenesis; however, whether these proteins impact adipogenesis remains to be addressed. In this study, we identify Prrx1a and Prrx1b as negative regulators of adipogenesis. We show that Prrx1a and Prrx1b are down-regulated during adipogenesis in vitro and in vivo. Stable knockdown of Prrx1a/b enhances adipogenesis, with increased expression of peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer-binding protein-alpha and FABP4 and increased secretion of the adipokines adiponectin and chemerin. Although stable low-level expression of Prrx1a, Prrx1b, or Prrx2 does not affect 3T3-L1 adipogenesis, transient overexpression of Prrx1a or Prrx1b inhibits peroxisome proliferator-activated receptor-gamma activity. Prrx1 knockdown decreases expression of Tgfb2 and Tgfb3, and inhibition of TGF beta signaling during adipogenesis mimics the effects of Prrx1 knockdown. These data support the hypothesis that endogenous Prrx1 restrains adipogenesis by regulating expression of TGF beta ligands and thereby activating TGF beta signaling. Finally, we find that expression of Prrx1a or Prrx1b in adipose tissue increases during obesity and strongly correlates with Tgfb3 expression in BL6 mice. These observations suggest that increased Prrx1 expression may promote TGF beta activity in adipose tissue and thereby contribute to aberrant adipocyte function during obesity.