脂肪细胞 NCoR 敲除可减少 PPARγ 磷酸化，增强 PPARγ 活性和胰岛素敏感性。
Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity.
机构信息
Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
出版信息
Cell. 2011 Nov 11;147(4):815-26. doi: 10.1016/j.cell.2011.09.050.
Insulin resistance, tissue inflammation, and adipose tissue dysfunction are features of obesity and Type 2 diabetes. We generated adipocyte-specific Nuclear Receptor Corepressor (NCoR) knockout (AKO) mice to investigate the function of NCoR in adipocyte biology, glucose and insulin homeostasis. Despite increased obesity, glucose tolerance was improved in AKO mice, and clamp studies demonstrated enhanced insulin sensitivity in liver, muscle, and fat. Adipose tissue macrophage infiltration and inflammation were also decreased. PPARγ response genes were upregulated in adipose tissue from AKO mice and CDK5-mediated PPARγ ser-273 phosphorylation was reduced, creating a constitutively active PPARγ state. This identifies NCoR as an adaptor protein that enhances the ability of CDK5 to associate with and phosphorylate PPARγ. The dominant function of adipocyte NCoR is to transrepress PPARγ and promote PPARγ ser-273 phosphorylation, such that NCoR deletion leads to adipogenesis, reduced inflammation, and enhanced systemic insulin sensitivity, phenocopying the TZD-treated state.
胰岛素抵抗、组织炎症和脂肪组织功能障碍是肥胖和 2 型糖尿病的特征。我们生成了脂肪细胞特异性核受体共抑制因子（NCoR）敲除（AKO）小鼠，以研究 NCoR 在脂肪细胞生物学、葡萄糖和胰岛素稳态中的功能。尽管肥胖程度增加，但 AKO 小鼠的葡萄糖耐量得到改善，钳夹研究表明肝脏、肌肉和脂肪的胰岛素敏感性增强。脂肪组织巨噬细胞浸润和炎症也减少。AKO 小鼠脂肪组织中的 PPARγ 反应基因上调，CDK5 介导的 PPARγ 丝氨酸-273 磷酸化减少，形成持续激活的 PPARγ 状态。这表明 NCoR 是一种衔接蛋白，可增强 CDK5 与 PPARγ 结合和磷酸化的能力。脂肪细胞 NCoR 的主要功能是反式抑制 PPARγ 并促进 PPARγ 丝氨酸-273 磷酸化，因此 NCoR 缺失导致脂肪生成减少、炎症减轻和全身胰岛素敏感性增强，模拟了 TZD 治疗状态。
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