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

Cell Metab. 2020 Oct 6;32(4):665-675.e6. doi: 10.1016/j.cmet.2020.08.016. Epub 2020 Sep 16.


The thiazolidinediones (TZDs) are ligands of PPARγ that improve insulin sensitivity, but their use is limited by significant side effects. Recently, we demonstrated a mechanism wherein TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPARγ at serine 273. However, the role of this modification hasn't been tested genetically. Here we demonstrate that mice encoding an allele of PPARγ that cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm insulin sensitivity. RNA-seq in these mice reveals reduced expression of Gdf3, a BMP family member. 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 phosphorylation and focus attention on a putative target, Gdf3.

Keywords: BMP; GDF3; PPARγ; TGF-β; adipose tissue; diabetes; inflammation; insulin resistance; macrophage; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cells, Cultured
  • Growth Differentiation Factor 3 / genetics
  • Growth Differentiation Factor 3 / metabolism*
  • Humans
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy*
  • Obesity / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Phosphorylation / drug effects
  • Thiazolidinediones / pharmacology*


  • Growth Differentiation Factor 3
  • PPAR gamma
  • Thiazolidinediones