Obesity-Linked PPAR? S273 Phosphorylation Promotes Insulin Resistance through
Growth Differentiation Factor 3.
Authors Hall JA, Ramachandran D, Roh HC, DiSpirito JR, Belchior T, Zushin PH, Palmer C,
Hong S, Mina AI, Liu B, Deng Z, Aryal P, Jacobs C, Tenen D, Brown CW, Charles
JF, Shulman GI, Kahn BB, Tsai LTY, Rosen ED, Spiegelman BM, Banks AS
Submitted By Submitted Externally on 10/12/2020
Status Published
Journal Cell Metabolism
Year 2020
Date Published 10/1/2020
Volume : Pages 32 : 665 - 675.e6
PubMed Reference 32941798
Abstract The thiazolidinediones (TZDs) are ligands of PPAR? 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
PPAR? at serine 273. However, the role of this modification hasn't been tested
genetically. Here we demonstrate that mice encoding an allele of PPAR? 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 PPAR? S273
phosphorylation and focus attention on a putative target, Gdf3.

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