Insulin resistance is a major factor in obesity-linked type 2 diabetes. PPARγ is a master regulator of adipogenesis, and small molecule agonists, termed thiazolidinediones, are potent therapeutic insulin sensitizers. Here, we studied the role of transcriptional co-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 constitutively active PPARγ state. Obese TAZ AKO mice show improved glucose tolerance and insulin sensitivity compared to littermate controls. PPARγ response genes are upregulated in 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 dependent on ERK-mediated Ser112 PPARγ phosphorylation. As adipocyte PPARγ Ser112 phosphorylation is increased in obesity, repression of PPARγ activity by TAZ could contribute to insulin resistance. These results identify TAZ as a new factor in the development of obesity-induced insulin resistance.

中文翻译：

---

TAZ是脂肪细胞中PPARγ活性的负调节剂，而TAZ缺失可改善胰岛素敏感性和葡萄糖耐量。

胰岛素抵抗是肥胖相关的2型糖尿病的主要因素。PPARγ是脂肪形成的主要调节剂，称为噻唑烷二酮的小分子激动剂是有效的治疗性胰岛素敏化剂。在这里，我们研究了具有PDZ结合基序（TAZ）的转录共激活因子作为PPARγ转录共抑制因子的作用。我们发现，脂肪细胞特异性TAZ基因敲除（TAZ AKO）小鼠表现出组成型活性PPARγ状态。与同窝对照相比，肥胖的TAZ AKO小鼠表现出更高的葡萄糖耐量和胰岛素敏感性。在来自TAZ AKO小鼠的脂肪组织中，PPARγ反应基因被上调，并且脂肪组织的炎症也有所减轻。体外和体内机制研究表明，TAZ-PPARγ相互作用部分取决于ERK介导的Ser112PPARγ磷酸化。由于肥胖中脂肪细胞PPARγSer112的磷酸化增加，因此TAZ抑制PPARγ活性可能有助于胰岛素抵抗。这些结果表明，TAZ是肥胖诱导的胰岛素抵抗发展的新因素。