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》。
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
Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
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