br FREE FATTY ACID RECEPTOR GPR br

FREE FATTY ACID RECEPTOR 1 (GPR40)
G-PROTEIN-COUPLED RECEPTOR 120
CONCLUSION Free fatty Lsodren synthesis receptors whose natural ligands are identified as FFAs having various lengths have been reported. They act as novel nutrient sensing receptors independent of PPARs and FABPs, and they are known to mediate a range of important processes controlling metabolic homeostasis. They also monitor FFA levels in the intestine, pancreas, macrophage, and adipose tissue (Fig. 2). Among the FFARs, FFAR1 and GPR120 are considered to be potential drug targets for the treatment of metabolic diseases such as type 2 diabetes because their physiological functions are related to energy homeostasis. Directly monitoring the interaction of FFAs with FFARs is considered difficult because of the high nonspecific binding and the low affinity of FFAs. However, we have successfully developed a FFAR1 binding assay method using flow cytometry and specific fluorescent-labeled FFAs, and this has been used to directly measure the binding of ligands to FFAR1. To elucidate the physiological functions of FFARs, it is necessary to detect both mRNA and protein expression. By using the gene knockout mouse and specific antibodies developed in our laboratory, we confirmed that GPR120 protein is expressed in adipocytes and in the lungs. In addition to the tissue expression profile of GPR120, some research groups developed selective ligands for FFAR1 and GPR120. Moreover, we reported the structure–activity relationship of GPR120 ligands and developed a specific synthetic ligand for GPR120 that showed potent activity both in vitro and in vivo. Further studies utilizing selective ligands, specific antibodies, flow-cytometry assays, and knockout mice may elucidate novel pharmacological and physiological functions of FFARs in metabolic homeostasis. Further analysis of FFARs may also be important to understand better the nutrient sensing process and to develop novel therapeutic compounds to treat metabolic diseases.
Acknowledgements
Introduction In the past two decades, enhanced understanding of the biology of G-protein-coupled receptors (GPR) has led to the identification of several such receptors as novel targets for free fatty acids (FFAs) [1]. The FFAs are the ligands for GPR40 (FFAR1), GPR43 (FFAR2), GPR41 (FFAR3), GPR120 (FFAR4), GPR119, and GPR84; the binding of FFAs to receptors varies depending on the number of carbons and unsaturated bonds in a molecular structure. FFAR1 and FFAR4, both coupled with a G-protein α-subunit of the Gq family, recognize medium- and long-chained FFAs, respectively. FFAR1 and FFAR4 have received special attention in the context of chronic metabolic and cardiovascular diseases, thanks to their endocrine and anti-inflammatory activities. Importantly, in vitro data suggest that, in different cell types (e.g., adipocytes, hepatocytes, muscles, epithelial cells, and macrophages), stimulation of FFAR1 and FFAR4 by ω-3 and ω-9 PUFAs exerts potent anti-inflammatory action. Oh et al., in an elegant paper, demonstrated that in vitro stimulation of macrophage FFAR4 by ω-3 PUFAs or a synthetic agonist (GW9508) caused a broad anti-inflammatory response by interfering with the LPS- and TNF-α-induced signaling cascades [2]. Moreover, upon activation of FFAR4, the expression of several inflammatory genes and markers in macrophages was significantly altered, pointing to a shift from a pro-inflammatory M1-like activation state toward an anti-inflammatory, pro-resolution, M2-like phenotype [2]. Yan et al. found that stimulation of macrophage FFAR1 and FFAR4 with ω-3 PUFAs inhibited the NLRP3 inflammasome and its subsequent IL-1β secretion [3]. Finally, both FFAR1 and FFAR4 have been linked with the downstream activation of 5’AMP-activated protein kinase (AMPK), which orchestrates a metabolic reprogramming of macrophages between M1- and M2-like activation states [4].