GPR120 Is an Omega-3 Fatty Acid Receptor Mediating Potent Anti-inflammatory and Insulin-Sensitizing Effects

Abstract

SUMMARY Omega-3 fatty acids (ω-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here we show that the G protein-coupled receptor 120 (GPR120) functions as an ω-3 FA receptor/sensor. Stimulation of GPR120 with ω-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high fat diet with or without ω-3 FA supplementation. The ω-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional ω-3 FA receptor/sensor and mediates potent insulin sensitizing and anti-diabetic effects in vivo by repressing macrophage-induced tissue inflammation.

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

“…Overexpressed GPR120 in these CRC cells was functional and signaled via a Gaq/11-coupled pathway, similar to GPR120-expressing RAW 264.7 cells and mature adipocytes. 8 In addition, GPR120 levels significantly correlated with clinical characteristics of CRC, including clinical stage, pathologic differentiation and lymph node metastasis. These observations prompted us to investigate the potential roles of GPR120-mediated signaling in the development of CRC.…”

“…GRP120 signaling induces angiogenesis in CRC cells through activation of the PI3K/Akt-NF-kB pathway GPR120 triggers various cellular pathways to exert disparate functions. 7,8 As the above-identified induced proangiogenic genes are known downstream targets of NF-kB, 16 we focused on the role of the NF-kB pathway in the production of proangiogenic mediators. First, we performed western blotting analysis to determine whether the NF-kB pathway was modulated by GPR120 signaling.…”

“…Activation of GPR120 enhances migration and induces EMT of CRC cells As recent evidence showed that o-3 fatty acid (FA) treatment can inhibit migration of primary WT macrophages by signaling through GPR120, 8 we sought to determine whether GPR120 signaling affects motility in CRC cells. We measured the migratory capability of HCT 116 and SW480 cells using an in vitro transwell chemotaxis assay.…”

“…32,33 However, it has been reported that GPR120 signaling inhibited the ability of primary macrophages to migrate toward adipocyte CM. 8 It seems a single GPCR can independently induce different effects in different cell types by different mechanisms. It would be of great interest to reveal the mechanistic differences in GPR120 signaling-induced effects in different cell types.…”

“…6,7 More recently, GPR120 has been shown to exert effects in regulating inflammation, mediating insulin sensitization and reducing obesity. 8,9 However, there is no report about the expression of GPR120 in tumors, and the role of GPR120 in tumor development is unknown, even though GPR120 is abundantly expressed in intestine.…”