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 effects1,2,3,4. 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 sensitivity5,6,7. 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 manner8. Indeed, genetic variants that predispose to obesity and diabetes have been described in the gene encoding GPR120 in humans (FFAR4)9. 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 receptor10, 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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Gene Expression Omnibus
This study was funded in part by grants to J.M.O. (DK033651, DK074868, DK063491 and DK09062) and D.Y.O. (P30 DK063491), a grant from Merck, Inc. to J.M.O. and D.Y.O., Austrian science fund (FWF Doktoratskolleg DK-MCD W1226 and the FWF project P24143) to J.G.B.-S., and a Marshall Plan Scholarship to A.R.P. We thank A. Tyler for editorial assistance and N. Sekiya for assistance with FACS analysis at the Veterans Affairs San Diego hospital, the University of California, San Diego (UCSD) Histology Core lab for technical help with processing liver specimens, and the UCSD Microscope Resource for microscopy analysis, which is funded by UCSD Neuroscience Microscopy Shared Facility Grant P30 NS047101.
Supplementary Figures 1–10