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Peroxisome Proliferator-activated Receptor (PPAR) gamma and G-protein Coupled Receptor 40 (GPCR40) Function as an Integrated Two-receptor Signaling Pathway

Thursday, October 11, 2012 — Poster Session III

10:00 a.m. – Noon

Natcher Conference Center, Building 45



* FARE Award Winner


  • K.S. Awad
  • S. Wang
  • R.L. Danner


PPARgamma is a type II nuclear receptor (NR) that regulates fatty acid storage and glucose metabolism. Ligand/agonists of PPARgamma such as rosiglitazone (RGZ) are insulin sensitizers used in the treatment of type 2 diabetes mellitus, but an incomplete understanding of PPARgamma signaling has hampered the development of safer, more effective drugs. Recently, RGZ was shown to activate stress kinase pathways through specific binding to G-protein coupled receptor 40 (GPCR40). Here, RGZ activation of GPCR40/p38 MAPK was found to control downstream PPARgamma signaling. RGZ activated p38 MAPK a human endothelial line and p38 inhibitor, siRNA knockdown (KD) and dominant-negative (DN) mutant over-expression impaired RGZ induction of PPARgamma signaling as measured by DNA binding and a PPAR response element-driven reporter gene. RGZ activation of p38 MAPK was GPCR40 dependent; GPCR40 inhibitor, siRNA KD, and over-expression of a DN Gq mutant all blocked RGZ activation of p38 MAPK. RGZ/GPCR40/p38 MAPK signaling led to ATF2 phosphorylation and subsequent PPARgamma acetylation. DN ATF2 blocked RGZ-induced PPARgamma activation, while a constitutively active ATF2 construct alone was associated with PPARgamma acetylation and activation. Unexplored effects through cognate GPCRs, as exemplified by this GPCR40/PPARgamma signaling pathway, could explain important safety and efficacy differences among NR-directed drugs.

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