2. Academic Validation
  3. A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice

A Gpr120-selective agonist improves insulin resistance and chronic inflammation in obese mice

  • Nat Med. 2014 Aug;20(8):942-7. doi: 10.1038/nm.3614.
Da Young Oh 1,  Evelyn Walenta 1,  Taro E Akiyama 2,  William S Lagakos 1,  Denise Lackey 1,  Ariane R Pessentheiner 3,  Roman Sasik 1,  Nasun Hah 4,  Tyler J Chi 1,  Jason M Cox 2,  Mary Ann Powels 2,  Jerry Di Salvo 2,  Christopher Sinz 2,  Steven M Watkins 5,  Aaron M Armando 6,  Heekyung Chung 1,  Ronald M Evans 7,  Oswald Quehenberger 8,  Joanne McNelis 1,  Juliane G Bogner-Strauss 9,  Jerrold M Olefsky 1
Affiliations

Affiliations

  • 1 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
  • 2 Merck Research Laboratories, Kenilworth, New Jersey, USA.
  • 3 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.
  • 4 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California, USA.
  • 5 Lipomics Technologies, West Sacramento, California, USA.
  • 6 Department of Pharmacology, University of California, San Diego, La Jolla, California, USA.
  • 7 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.
  • 8 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.
  • 9 Institute of Biochemistry, Graz University of Technology, Graz, Austria.
PMID: 24997608 DOI: 10.1038/nm.3614
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.

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