Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity

Vivian A. Paschoal, Evelyn Walenta, Saswata Talukdar, Ariane R. Pessentheiner, Olivia Osborn, Nasun Hah, Tyler J. Chi, George L. Tye, Aaron M. Armando, Ronald M. Evans, Nai Wen Chi, Oswald Quehenberger, Jerrold M. Olefsky, Da Young Oh

Research output: Contribution to journalArticle

Abstract

G protein-coupled receptor 120 (GPR120) and PPARγ agonists each have insulin sensitizing effects. But whether these two pathways functionally interact and can be leveraged together to markedly improve insulin resistance has not been explored. Here, we show that treatment with the PPARγ agonist rosiglitazone (Rosi) plus the GPR120 agonist Compound A leads to additive effects to improve glucose tolerance and insulin sensitivity, but at lower doses of Rosi, thus avoiding its known side effects. Mechanistically, we show that GPR120 is a PPARγ target gene in adipocytes, while GPR120 augments PPARγ activity by inducing the endogenous ligand 15d-PGJ2 and by blocking ERK-mediated inhibition of PPARγ. Further, we used macrophage- (MKO) or adipocyte-specific GPR120 KO (AKO) mice to show that GRP120 has anti-inflammatory effects via macrophages while working with PPARγ in adipocytes to increase insulin sensitivity. These results raise the prospect of a safer way to increase insulin sensitization in the clinic.

Original languageEnglish (US)
Pages (from-to)1173-1188.e5
JournalCell Metabolism
Volume31
Issue number6
DOIs
StatePublished - Jun 2 2020

Keywords

  • 15d-PGJ2
  • Compound A
  • GPR120
  • PPARγ
  • combination therapy
  • insulin resistance
  • thiazolidinedione
  • type 2 diabetes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Paschoal, V. A., Walenta, E., Talukdar, S., Pessentheiner, A. R., Osborn, O., Hah, N., Chi, T. J., Tye, G. L., Armando, A. M., Evans, R. M., Chi, N. W., Quehenberger, O., Olefsky, J. M., & Oh, D. Y. (2020). Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity. Cell Metabolism, 31(6), 1173-1188.e5. https://doi.org/10.1016/j.cmet.2020.04.020