美国加州大学圣地亚哥分校Jerrold M. Olefsky研究团队发现，PDZ结合结构域（TAZ）是脂肪细胞中PPARγ活性的负调节剂，TAZ缺失可改善胰岛素敏感性和葡萄糖耐受。11月7日，《细胞—代谢》在线发表了这一成果。

研究人员发现，具有PDZ结合结构域（TAZ）的转录共激活因子，可以发挥PPARγ转录共抑制因子的作用。脂肪细胞特异性TAZ基因敲除（TAZ AKO）的小鼠，表现出组成型激活PPARγ的状态。与同窝小鼠相比，肥胖的TAZ AKO小鼠表现出更高的葡萄糖耐受和胰岛素敏感性。TAZ AKO小鼠脂肪组织中的PPARγ应答基因上调，并且脂肪组织的炎症也有所减轻。体外和体内的机制研究表明，TAZ-PPARγ相互作用部分取决于ERK介导的PPARγ Ser112的磷酸化。由于肥胖人群脂肪细胞中PPARγ Ser112的磷酸化增加，因此TAZ抑制PPARγ活性可能加剧了胰岛素抵抗。这些结果表明，TAZ是造成肥胖诱导的胰岛素抵抗的新因素。

据介绍，胰岛素抵抗是肥胖相关的2型糖尿病的主要因素。PPARγ是脂肪生成的主要调节因子，小分子激动剂噻唑烷二酮是有效的胰岛素增敏剂。

附：英文原文

Title: TAZ Is a Negative Regulator of PPARγ Activity in Adipocytes and TAZ Deletion Improves Insulin Sensitivity and Glucose Tolerance

Author: Dalila El Ouarrat, Roi Isaac, Yun Sok Lee, Da Young Oh, Joshua Wollam, Denise Lackey, Matthew Riopel, Gautam Bandyopadhyay, Jong Bae Seo, Revathy Sampath-Kumar, Jerrold M. Olefsky

Issue&Volume: November 07, 2019

Abstract: Insulin resistance is a major factor in obesity-linked type 2 diabetes. PPARγ is amaster regulator of adipogenesis, and small molecule agonists, termed thiazolidinediones,are potent therapeutic insulin sensitizers. Here, we studied the role of transcriptionalco-activator with PDZ-binding motif (TAZ) as a transcriptional co-repressor of PPARγ.We found that adipocyte-specific TAZ knockout (TAZ AKO) mice demonstrate a constitutivelyactive PPARγ state. Obese TAZ AKO mice show improved glucose tolerance and insulinsensitivity compared to littermate controls. PPARγ response genes are upregulatedin adipose tissue from TAZ AKO mice and adipose tissue inflammation was also decreased.In vitro and in vivo mechanistic studies revealed that the TAZ-PPARγ interaction is partially dependenton ERK-mediated Ser112 PPARγ phosphorylation. As adipocyte PPARγ Ser112 phosphorylationis increased in obesity, repression of PPARγ activity by TAZ could contribute to insulinresistance. These results identify TAZ as a new factor in the development of obesity-inducedinsulin resistance.

DOI: 10.1016/j.cmet.2019.10.003

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30558-3