@article{bfc3ca838d8146938a71d7f4461d5024,
title = "Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity",
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.",
keywords = "15d-PGJ2, Compound A, GPR120, PPARγ, combination therapy, insulin resistance, thiazolidinedione, type 2 diabetes",
author = "Paschoal, {Vivian A.} and Evelyn Walenta and Saswata Talukdar and Pessentheiner, {Ariane R.} and Olivia Osborn and Nasun Hah and Chi, {Tyler J.} and Tye, {George L.} and Armando, {Aaron M.} and Evans, {Ronald M.} and Chi, {Nai Wen} and Oswald Quehenberger and Olefsky, {Jerrold M.} and Oh, {Da Young}",
note = "Funding Information: We thank Bruce Spiegelman (Harvard Medical School) for sharing the PPARγ phosphor-S273 antibody and Robert Lefkowitz (Duke University, HHMI) for providing GFP-tagged β arrestin-2 and RFP-tagged ERK2 plasmids. We thank Angela Tyler and Jachelle Pimentel for editorial assistance, the UCSD Histology Core lab for processing adipose tissue specimens, and the UCSD Microscope Resource (funded by UCSD Neuroscience Microscopy Shared Facility Grant P30 NS047101 ) for confocal microscopy analysis. This work was supported by grants from the NIH ( R01 DK108773 to D.Y.O.; P01DK054441 and P30DK063491 to J.M.O.), the American Heart Association ( 14SDG19880020 to D.Y.O.), and the American Diabetes Association Minority Postdoctoral Fellowship ( 1-18-PMF-030 to V.A.P.). Funding Information: We thank Bruce Spiegelman (Harvard Medical School) for sharing the PPAR? phosphor-S273 antibody and Robert Lefkowitz (Duke University, HHMI) for providing GFP-tagged ? arrestin-2 and RFP-tagged ERK2 plasmids. We thank Angela Tyler and Jachelle Pimentel for editorial assistance, the UCSD Histology Core lab for processing adipose tissue specimens, and the UCSD Microscope Resource (funded by UCSD Neuroscience Microscopy Shared Facility Grant P30 NS047101) for confocal microscopy analysis. This work was supported by grants from the NIH (R01 DK108773 to D.Y.O.; P01DK054441 and P30DK063491 to J.M.O.), the American Heart Association (14SDG19880020 to D.Y.O.), and the American Diabetes Association Minority Postdoctoral Fellowship (1-18-PMF-030 to V.A.P.). D.Y.O. conceived the project and designed the studies. D.Y.O. and V.A.P. performed most of the experiments. V.A.P. and E.W. performed hyperinsulinemic-euglycemic clamps. S.T. performed ob/ob mice experiments. O.O. performed RNA-seq and microarray data analysis. N.H. analyzed ChIP-seq database. A.M.A. and O.Q. performed liquid chromatography-mass spectrometry for eicosanoid measurement. A.R.P. T.J.C. and G.L.T. assisted with experiments. N.W.C. reviewed the manuscript and contributed discussions. R.M.E. contributed discussions. D.Y.O. and J.M.O. analyzed and interpreted data, and co-wrote this manuscript. The authors declare no competing financial interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = jun,
day = "2",
doi = "10.1016/j.cmet.2020.04.020",
language = "English (US)",
volume = "31",
pages = "1173--1188.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}