FFA4 receptor (GPR120): A hot target for the development of anti-diabetic therapies

Abstract

Free Fatty Acid 4 receptor (FFA4 receptor or GPR120), a rhodopsin-like G protein coupled receptor (GPCR) subfamily member, is a receptor that senses specific fatty acids such as ω-3 fatty acid in fish oil or the endogenous signaling lipid, PHASA. FFA4 receptor is enriched in lung, colon and adipose tissue but is also detected in many other tissues and cells. The activation of FFA4 receptor has multiple effects, including but not limited to inhibition of inflammation, improving insulin sensitivity and adipogenesis, and regulating hormone secretion from the gastro-intestinal system and pancreatic islets. The important role of FFA4 receptor in maintaining metabolic homeostasis strongly indicates the great potential of selective FFA4 receptor agonizts to treat diabetes and inflammation. In this review, we summarize recent research progress in the physiological and biochemical studies of FFA4 receptor and highlight its underlying signaling mechanisms and ligand identification to assist future research to exploit FFA4 receptor as a drug target.

Introduction

G protein-coupled receptors (GPCRs) are the largest protein superfamily in the human genome and are important regulators of a variety of physiological actions. Although the inappropriate expression or mutation of specific GPCRs causes human diseases, pharmacological treatments targeting GPCRs can rescue certain dysfunctions and improve human health. To date, GPCRs are the largest protein family of clinical drug targets, and significant endeavors have been undertaken to develop new strategies to determine their clinical potentials.

Over the last two decades, ligands that activate GLP-1 receptor (GLP-1R) or inhibit dipeptidyl peptidase4 (DPP4) have been successfully used to treat diabetes, which is one of the most prevalent human diseases in the modern world (Ahren, 2009, Hu, 2011). These achievements have encouraged scientists to search for additional strategies to modulate other GPCR activities and thereby restore metabolic homeostasis (Tiwari, 2010, Heng et al., 2013, Lieu et al., 2014). The FFA4 receptor, also called free fatty acid receptor 4 (FFAR4 or GPR120), which is the mammalian receptor for both ω-3 fatty acids from fish products and a newly identified endogenous signaling lipid, palmitic acid-hydroxy stearic acid (PAHSA), have received enormous attention for their potential to treat diabetes (Oh et al., 2010, Ussar and Tschop, 2014, Yore et al., 2014). FFA4 receptor belongs to the rhodopsin subfamily of GPCRs and is widely expressed in many tissues (Fredriksson et al., 2003, Wellendorph et al., 2009, Hirasawa et al., 2011, Zhang and Leung, 2014). Recent studies have discovered that FFA4 receptor is a multifunctional protein that improves many aspects of metabolic homeostasis, such as insulin sensitivity, macrophage functions, hepatic steatosis and hormone secretion from the pancreatic islets or intestinal endocrine cells (Oh et al., 2010, Li et al., 2013, Yan et al., 2013, Liu et al., 2014, Oh da et al., 2014, Raptis et al., 2014). Interestingly, at least two types of cellular signaling pathways downstream of FFA4 receptor, the G_αq-mediated signaling pathway and the β-arrestin-dependent pathway, were identified as facilitating the functions of FFA4 receptor in different cell types or tissues. In addition to endogenous or natural lipids, many ligands that directly activate FFA4 receptor have been developed (Shimpukade et al., 2012, Hudson et al., 2013, Hudson et al., 2014, Oh da et al., 2014, Sparks et al., 2014). In this mini review, we discuss the current knowledge regarding the structure, function, signaling and ligand properties of FFA4 receptor, which may illuminate future research to exploit new therapeutic potentials.