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

It is well known that the omega-3 fatty acids (ω3-FAs) contained in fish oils can exert potent anti-inflammatory effects 1-4. ω3-FAs are commonly consumed as fish products, dietary supplements, and pharmaceuticals and a number of health benefits have been ascribed to them, including a reduction in plasma triglyceride levels, amelioration of atherosclerosis, and increased insulin sensitivity 5-7. We reported that Gpr120 is the functional receptor/sensor for these fatty acids and that ω3-FAs produce robust anti-inflammatory, insulin sensitizing effects, both in vivo and in vitro in a Gpr120-dependent manner 8. Indeed, human genetic variants in the Gpr120 gene had been described which predispose to obesity and diabetes 9. However, the amount of fish oils which 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 GPCR 10, and it has been difficult to identify compounds with a high degree of selectivity for Gpr120 vs. Gpr40 11. Here we report that a high affinity, selective, 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 (HFD)/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.