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肥胖相关的PPARγ S273磷酸化通过生长分化因子3促进胰岛素抵抗
作者:小柯机器人 发布时间:2020/9/18 15:48:56

美国哈佛医学院Alexander S. Banks小组发现,肥胖相关的PPARγ S273磷酸化通过生长分化因子3促进胰岛素抵抗。该研究于2020年9月16日在线发表于国际一流学术期刊《细胞—代谢》。

研究人员表示,噻唑烷二酮(TZD)是PPARγ的配体,可提高胰岛素敏感性,但其使用受到明显副作用的限制。最近,研究人员证明了一种TZD改善胰岛素敏感性但不同于受体激动和脂肪生成的机制:肥胖相关的PPARγ在丝氨酸273磷酸化的逆转。但是,这种修饰的作用尚未经过基因测试。
 
研究人员证明,编码在S273不能磷酸化的PPARγ等位基因小鼠受到胰岛素抵抗的保护,而没有表现出体重差异或与TZD相关的副作用。实际上,高胰岛素-正常血糖钳夹实验证实了胰岛素敏感性。这些小鼠中的RNA-seq显示BMP家族成员Gdf3的表达减少。df3的异位表达足以在非肥胖健康小鼠中诱导胰岛素抵抗。研究人员发现Gdf3在体外抑制BMP信号传导和胰岛素信号传导。
 
总之,这些结果突出了PPARγ S273磷酸化的致糖尿病作用,并将注意力集中在可能的靶标Gdf3上。
 
附:英文原文

Title: Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3

Author: Jessica A. Hall, Deepti Ramachandran, Hyun C. Roh, Joanna R. DiSpirito, Thiago Belchior, Peter-James H. Zushin, Colin Palmer, Shangyu Hong, Amir I. Mina, Bingyang Liu, Zhaoming Deng, Pratik Aryal, Christopher Jacobs, Danielle Tenen, Chester W. Brown, Julia F. Charles, Gerald I. Shulman, Barbara B. Kahn, Linus T.Y. Tsai, Evan D. Rosen, Bruce M. Spiegelman, Alexander S. Banks

Issue&Volume: 2020-09-16

Abstract: The thiazolidinediones (TZDs) are ligands of PPARγ that improve insulin sensitivity,but their use is limited by significant side effects. Recently, we demonstrated amechanism wherein TZDs improve insulin sensitivity distinct from receptor agonismand adipogenesis: reversal of obesity-linked phosphorylation of PPARγ at serine 273.However, the role of this modification hasn’t been tested genetically. Here we demonstratethat mice encoding an allele of PPARγ that cannot be phosphorylated at S273 are protectedfrom insulin resistance, without exhibiting differences in body weight or TZD-associatedside effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm insulinsensitivity. RNA-seq in these mice reveals reduced expression of Gdf3, a BMP familymember. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean,healthy mice. We find Gdf3 inhibits BMP signaling and insulin signaling in vitro. Together, these results highlight the diabetogenic role of PPARγ S273 phosphorylationand focus attention on a putative target, Gdf3.

DOI: 10.1016/j.cmet.2020.08.016

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30476-9

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx