Pharmacological Characterization of GPR120 Ligands

Abstract

Omega-3 fatty acids (ω-3 FAs) and other long chain free fatty acids activate GPR120, which has been shown to mediate some of the anti-inflammatory effects of ω-3 FAs. Loss-of-function mutation in human GPR120 confers increased risk for obesity and GPR120 deficient mice develop diet induced obesity, glucose intolerance and fatty liver disease. The goal of the current study was to understand GPR120 ligand selectivity by testing agonist activity of various fatty acids in cell based assays to measure G-protein activated second messengers, β-arrestin recruitment and inhibition of cytokine production. HEK 293 cells over-expressing GPR120 and Gα15 were used to detect agonist mediated IP-1 production and measure intracellular Ca2+. β-arrestin recruitment was measured using DiscoveRx enzyme complementation technology. GPR120 agonist mediated inhibition of LPS-induced cytokine production was measured in the RAW 264.7 cells. We confirmed the previously reported agonist activity of ω-3 FAs including DHA, EPA, α-linolenic acid and other polyunsaturated fatty acids such as palmitoleate and oleic acid. However, in contrast to earlier reports ω-6 FAs linoleic acid, arachidonic acid and γ-linolenic acid were found to robustly activate GPR120 signaling. Further characterization of GPR120 ligands will help understand its physiological role and determine its potential as a therapeutic target.