title: A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice.
abstract: It is well known that the ω-3 fatty acids (ω-3-FAs; also known as n-3 fatty acids) can exert potent anti-inflammatory effects. Commonly consumed as fish products, dietary supplements and pharmaceuticals, ω-3-FAs have a number of health benefits ascribed to them, including reduced plasma triglyceride levels, amelioration of atherosclerosis and increased insulin sensitivity. We reported that Gpr120 is the functional receptor for these fatty acids and that ω-3-FAs produce robust anti-inflammatory, insulin-sensitizing effects, both in vivo and in vitro, in a Gpr120-dependent manner. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4). However, the amount of fish oils that would have to be consumed to sustain chronic agonism of Gpr120 is too high to be practical, and, thus, a high-affinity small-molecule Gpr120 agonist would be of potential clinical benefit. Accordingly, Gpr120 is a widely studied drug discovery target within the pharmaceutical industry. Gpr40 is another lipid-sensing G protein-coupled receptor, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 over Gpr40 (ref. 11). Here we report that a selective high-affinity, orally available, small-molecule Gpr120 agonist (cpdA) exerts potent anti-inflammatory effects on macrophages in vitro and in obese mice in vivo. Gpr120 agonist treatment of high-fat diet-fed obese mice causes improved glucose tolerance, decreased hyperinsulinemia, increased insulin sensitivity and decreased hepatic steatosis. This suggests that Gpr120 agonists could become new insulin-sensitizing drugs for the treatment of type 2 diabetes and other human insulin-resistant states in the future.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Walenta
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Taro E
authors.initials: TE
authors.lastname: Akiyama
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Lagakos
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Lackey
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA. [2] Institute of Biochemistry, Graz University of Technology, Graz, Austria.
authors.forename: Ariane R
authors.initials: AR
authors.lastname: Pessentheiner
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Sasik
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Chi
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Cox
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Powels
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.affiliation: Merck Research Laboratories, Kenilworth, New Jersey, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sinz
authors.affiliation: Lipomics Technologies, West Sacramento, California, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Watkins
authors.affiliation: Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Armando
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Chung
authors.affiliation: 1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA. [2] Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA. [2] Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: McNelis
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Graz, Austria.
authors.forename: Juliane G
authors.initials: JG
authors.lastname: Bogner-Strauss
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D060151:B-Lymphocytes, Regulatory / Q000276:immunology; D001483:Base Sequence; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005234:Fatty Liver / Q000188:drug therapy; D006946:Hyperinsulinism / Q000188:drug therapy; D007249:Inflammation; D007333:Insulin Resistance / Q000502:physiology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008969:Molecular Sequence Data; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D009765:Obesity / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: C498007:FFAR4 protein, mouse; D015525:Fatty Acids, Omega-3; C473036:Ffar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D004281:Docosahexaenoic Acids; D052247:Nitric Oxide Synthase Type II; D001119:Arginase