Positive Reinforcing Mechanisms between GPR120 and PPARγ Modulate Insulin Sensitivity.

Autor:	Paschoal VA; Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Walenta E; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Talukdar S; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Merck & Co., Inc., SSF, 630 Gateway Boulevard, South San Francisco, CA 94080, USA., Pessentheiner AR; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Osborn O; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Hah N; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Chi TJ; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Tye GL; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, OH 44106, USA., Armando AM; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA., Evans RM; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Chi NW; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; VA San Diego Healthcare System, San Diego, CA, USA., Quehenberger O; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA., Olefsky JM; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jolefsky@health.ucsd.edu., Oh DY; Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dayoung.oh@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2020 Jun 02; Vol. 31 (6), pp. 1173-1188.e5. Date of Electronic Publication: 2020 May 14.
DOI:	10.1016/j.cmet.2020.04.020
Abstrakt:	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. Competing Interests: Declaration of Interests The authors declare no competing financial interests. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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