The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function
The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function
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DOI：
10.2337/db17-0318
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发表时间：
2018-04-01
期刊：
影响因子：
7.7
通讯作者：
Norton, Luke
中科院分区：
文献类型：
--
作者：
Chen, Xi;Ayala, Iriscilla;Norton, Luke
转录因子7样2（TCF 7 L2）基因编码是迄今发现的最强的2型糖尿病（T2 DM）候选基因。TCF 7 L2蛋白是Wnt/β-catenin信号通路的关键转录效应子，Wnt/β-catenin信号通路是负调节脂肪形成的重要发育通路。然而，TCF 7 L2在脂肪细胞的发育和功能中所起的确切作用在很大程度上仍然未知。使用体外方法的组合，我们首先表明，TCF 7 L2蛋白在3 T3-L1细胞和原代脂肪干细胞的脂肪形成过程中增加，并且TCF 7 L2表达是脂肪形成过程中Wnt信号调节所必需的。通过去除体内成熟脂肪细胞中的高迁移率族（HMG）-盒DNA结合结构域来灭活TCF 7 L2蛋白导致全身葡萄糖耐受不良和肝脏胰岛素抵抗。这种表型与皮下脂肪组织质量增加、脂肪细胞肥大和炎症相关。最后，我们证明，TCF 7 L2 mRNA表达下调，在人类与糖耐量受损和脂肪细胞胰岛素抵抗，突出了这些发现的翻译潜力。总之，我们的数据表明，TCF 7 L2在脂肪组织发育和功能中具有关键作用，这可能至少部分揭示TCF 7 L2如何促进T2 DM的病理生理学。
The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. Finally, we demonstrate that TCF7L2 mRNA expression is downregulated in humans with impaired glucose tolerance and adipocyte insulin resistance, highlighting the translational potential of these findings. In summary, our data indicate that TCF7L2 has key roles in adipose tissue development and function that may reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.