Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders

Abstract

Over the last decade, a subfamily of G protein-coupled receptors that are agonized by endogenous and dietary free-fatty acids (FFA) has been discovered. These free-fatty acid receptors include FFA2 and FFA3, which are agonized by short-chained FFA, as well as FFA1 and FFA4, which are agonized by medium-to-long chained FFA. Ligands for FFA1 and FFA4 comprise the family of long chain polyunsaturated omega-3 fatty acids including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), suggesting that many of the long-known beneficial effects of these fats may be receptor mediated. In this regard, FFA4 has gathered considerable interest due to its role in ameliorating inflammation, promoting insulin sensitization, and regulating energy metabolism in response to FFA ligands. The goal of this review is to summarize the body of evidence in regard to FFA4 signal transduction, its mechanisms of regulation, and its functional role in a variety of tissues. In addition, recent endeavors toward discovery of small molecules that modulate FFA4 activity are also presented.

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

“…Due to its more ubiquitous expression, much more work has been published on the shorter FFA4 isoform (12), while very little has been described regarding the function of FFA4-L. A study published in 2012 showed that agonism of FFA4-S transiently expressed in HEK-293 cells could signal via both Gαq/11 and β-arrestin-2 cascades, while importantly, agonism of FFA-L was incapable of promoting Ca 2+ -dependent signals via Gαq/11, yet could signal fully via β-arrestin-2 (17). Our results shed further light on differences in signal capabilities of the two FFA4 isoforms.…”

“…These free-fatty acid receptors include FFA2 and FFA3, which are agonized by short-chained FFA, as well as FFA1 and FFA4, which are agonized by medium-to-long chained FFA. FFA4, previously termed GPR120, has recently drawn considerable attention due to its profound anti-inflammatory effects (reviewed in 12). Oh and colleagues recently demonstrated that FFA4 agonism can reverse LPS-induced activation of NF-κB and inhibit release of proinflammatory IL-6 and TNF–α from macrophages, in a manner dependent on interaction with β-arrestin-2 partner proteins (13).…”

Oral administration of the selective GPR120/FFA4 agonist compound A is not effective in alleviating tissue inflammation in mouse models of prototypical autoimmune diseases

“…This concept of the molecular mode of action of ω3‐PUFAs has been extended by another putatively most important mechanism since DHA and EPA were identified as cognate ligands of the G protein‐coupled receptor (GPCR) 120. GPR120 was deorphanized in 2005 to bind the ω3‐PUFAs docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), and α‐linolenic acid as well as palmitoleic, myristic, and linoleic acid as agonistic, cognate ligands . It was subsequently renamed Free Fatty Acid receptor 4 (FFA4) by the International Union of Basic and Clinical Pharmacology .…”

“…To date, most extensively investigated physiological role of GPR120/FFA4 is its positive effect on insulin sensitivity, which has sparked broad interest into the development of GPR120/FFA4 agonists as novel antidiabetics . In recent years, it has been shown that FFA4 is also expressed on immune cells, including monocytes/macrophages, dendritic cells, and eosinophils, suggesting that GPR120/FFA4 may mediate immunomodulatory actions of ω3‐PUFAs. In line with this notion, in vitro activation of GPR120/FFA4 in macrophages curbs their immune response to NLPR3 inflammasome, TLR4, or TNF‐α activation, and in vivo GPR120 is required for ω3‐PUFAs to counteract adipose tissue inflammation induced by high‐fat diet in mice by limiting the recruitment of monocyte/macrophages into adipose and reducing the release of proinflammatory M1 macrophage‐derived immunomediators, such as IL‐1β, TNF‐α, MCP‐1, and IL‐6, while in parallel promoting the expression of antiinflammatory M2 macrophages, such as IL‐10, arginase 1, Ym‐1, and Clec7a .…”

Free Fatty Acid Receptor 1 (FFAR1) as an Emerging Therapeutic Target for Type 2 Diabetes Mellitus: Recent Progress and Prevailing Challenges

“…Among these potential targets, FFAR1 and FFAR4 are the most closely related to the regulation of glucose‐stimulated insulin secretion (GSIS) and other regulatory processes associated with T2DM. Readers interested in the pharmacology of FFARs may also refer to several comprehensive reviews . Of particular interest is FFAR1, which plays a key role in stimulating the release of incretins on enteroendocrine cells and amplifying GSIS on pancreatic β‐cells, suggesting that FFAR1 might be a promising antidiabetic target associated with low risk of hypoglycemia.…”