Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101625


Historical Background

G-protein-coupled receptors (GPCRs), also known as 7-transmemebrane domain receptors (7-TM receptors), have about 850 predicted members that act as cell surface messengers in response to extracellular signals, thus triggering intracellular signaling events (Kroeze et al. 2003). GPCRs are subject to activation by ligands, lights, hormones, neurotransmitters, odorants, or drug molecules, regulating various physiological functions including, but not limiting to, lipid metabolism and inflammation (Oh et al. 2010; Talukdar et al. 2011). Among these members, GPR120 was identified by searching the databases of rhodopsin-like GPCRs that belongs to the rhodopsin family of GPCRs and is conservative in human and mouse (Fredriksson et al. 2003). Until 2010, GPR120 was firstly reported to be an omega-3 fatty acid receptor, possessing anti-inflammatory as well as insulin-sensitizing effects (Oh et al. 2010). Free fatty acids (FFAs) act as ligands for several GPCRs, while GPR120 is activated by unsaturated medium- and long-chain FFAs. Since the discovery of GPR120 dysfunction-induced obesity in both humans and animals, this novel gene is considered a potentially therapeutic target with clinical merit for obesity and diabetes (Ichimura et al. 2012).

Distribution and Physiological Functions of GPR120

There are two isoforms of human GPR120, namely, the short form of 361 amino acid residues and the long form of 377 residues with 16 additional residues which were inserted in the third intracellular loop of the sequence. Cynomolgus monkey, mouse, and rat have one variant corresponding to the human short form (Watterson et al. 2014). GPR120 was identified to be widely expressed in many human tissues and cell types as well as rodent tissues, regulating various physiological functions (Fig. 1). In humans, GPR120 was expressed in both subcutaneous and omental adipose tissues; interestingly, GPR120 expression was significantly higher in obese individuals than in lean ones. To further explore the role of GPR120 in human obesity, this gene has been sequenced in more than 14,000 Europeans; two important non-synonymous variants, namely, R270H and R67C, were identified: R270H variant was strongly associated with obesity and insulin resistance, while R67C had a positive correlation with obesity (Ichimura et al. 2012). In addition, the deficiency of the GPR120 in mice affected basal metabolism. High-fat diet (HFD)-fed GPR120 knockout (KO) mice developed obesity, fatty liver, glucose intolerance, and insulin resistance. In adipose tissue of GPR120 KO mice, adipocyte differentiation and lipogenesis were decreased, but inflammation was enhanced. All of these observations contributed to the systemic metabolic disorders in GPR120 KO mouse (Ichimura et al. 2012). GPR120 was found to locate in type II taste cells in human and mouse that participated in appetite regulation in taste buds (Ozdener et al. 2014). GPR120-KO mice showed less preference for linoleic acid (LA) and oleic acid (OA), indicating that GPR120 serves as a sensor of fatty acids involved in the gustatory fatty acid perception. GPR120 was also reported to co-localize with the incretin glucagon-like peptide 1 (GLP-1), mediating GLP-1 release and thus probably contributing to food intake (Hirasawa et al. 2005). Furthermore, fatty acid might inhibit ghrelin secretion via GPR120 receptor in the central nervous system (CNS). Indeed, when GPR120 was knocked down by siRNA, the inhibition of ghrelin secretion was abolished (Gong et al. 2014). Meanwhile GPR120 was identified to be highly expressed in the intestines of humans and mice, regulating diverse hormonal secretion. For example, in STC-1 cells (a murine enteroendocrine cell line), GPR120 activation with LA, docosahexaenoic acid (DHA), or palmitoleic acid promoted the release of GLP-1. Moreover, FFAs also induced cholecystokinin (CCK) secretion through GPR120 in STC-1 cells (Tanaka et al. 2008). Glucose-dependent insulinotropic polypeptide (GIP) is another major incretin in the regulation of glucose homeostasis. GPR120 could increase the secretion of GIP that resulted in glucose-dependent insulin secretion (Kazakos 2011). The pancreas is one of the critical metabolic organs for energy metabolism; diabetes is a metabolic disease which is closely associated with islet dysfunction and β-cell loss. Recent studies have showed that GPR120 was expressed in human pancreatic islets and functions as a protective role in type 2 diabetes (T2D) (Taneera et al. 2012).Prior reports have demonstrated the expression and localization of GPR120 in pancreatic islet cell types. In mouse islet δ-cells, GPR120 was found to inhibit somatostatin secretion, while somatostatin is a hormone that has inhibitory action on the secretion of glucagon and insulin. GPR120 has also been shown to promote glucagon secretion from islet α-cells via activation of calcium signaling, as evidenced by GPR120 activation-induced insulin secretion in rat islets, INS-1E and MIN6 β-cells (Zhang et al. 2016).
GPR120, Fig. 1

Distribution and physiological functions of GPR120. GLP-1 glucagon-like peptide 1, CCK cholecystokinin, GIP glucose-dependent insulinotropic polypeptide

In 2010, Oh and co-workers demonstrated that GPR120 functions as unsaturated FFA receptors, which were highly expressed in RAW264.7 cells and primary mouse macrophages, mediating anti-inflammatory effects (Oh et al. 2010). It was observed that tissue inflammation was inhibited, and systemic insulin sensitivity was increased in HFD with ω-3 FA supplementation-fed WT mice but not GPR120 KO mice. Thus, macrophage-induced chronic inflammation plays an important role in obesity, and DHA is able to inhibit this inflammatory activation in macrophages via GPR120. Such GPR120-induced anti-inflammatory effects were also found in the hypothalamus and neurons. In human eosinophils, the stimulation of GPR120-induced IL-4 secretion inhibited caspase-3 activity with anti-apoptotic effects. An investigative study reported that GPR120 allele was significantly associated with the alanine transaminase levels in liver injury of obese children and adolescents (Marzuillo et al. 2014). Moreover, GPR120 was identified to mitigate hepatic stress via mediation of hepatoprotective effects in Kupffer cells (Raptis et al. 2014). Furthermore, GPR120 was expressed in the bone, including osteoblasts and osteoclasts, while unsaturated fatty acids stimulated osteoblastic bone formation and suppressed osteoclastic bone resorption. GPR120 was also highly expressed in the lung wherein its function has yet to be explored (Miyauchi et al. 2009).

Natural and Synthetic Agonists of GPR120

As defined, fatty acids are divided into short-chain fatty acids (C2–C6), medium-chain fatty acids (C7–C12), and long-chain fatty acids (C13–C22). It is well known that GPR120 can be stimulated by FAs, especially the long-chain fatty acids (Oh et al. 2010). Among the members of GPCRs, GPR41 and GPR43 are activated by short-chain fatty acids, GPR84 by medium-chain fatty acids, GPR119 by long-chain fatty acids, and GPR40 by medium-chain and long-chain fatty acids. Fatty acids are also classified into saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids (PUFAs). PUFAs consist mainly of the ω-3 fatty acids and ω-6 fatty acids, which are essential for a health. It was previously identified that GPR40 was activated by ω-3 fatty acids and ω-6 fatty acids. GPR120 was also found to be stimulated by similar FAs: they include ω-6-derived linoleic acid (LA, C18:2), ω-3-derived α-linolenic acid (ALA, C18:3), eicosapentaenoic acid (EPA, C20:5), and docosahexaenoic acid (DHA, C22:6) (see Table 1). ALA and DHA promoted GLP-1 secretion from the STC-1 enteroendocrine cells through stimulating GPR120 receptor. EPA and DHA mediated anti-inflammatory effects in macrophages and adipocytes via GPR120. The deficiency of GPR120 resulted in glucose intolerance, insulin insensitivity, and inflammation in obesity. The ω-3 and ω-6 PUFAs function as the natural ligands for GPR120 that is associated with various protective effects against metabolic disorders, via mediation of cell signalings and gene expressions (Mobraten et al. 2013). However, the ω-6 and ω-3 PUFAs cannot be obtained by de novo synthesis in humans, but only by dietary intake, such as from plant and fish oil.
GPR120, Table 1

Common natural and synthetic agonists of GPR120




EC50 (μM)



Plant oils



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Fish oils



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Synthetic agonists


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Compound A

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LA linoleic acid, ALA α-linolenic acid, EPA eicosapentaenoic acid, DHA docosahexaenoic acid

It is necessary to develop synthetic agonists to further identify the GPR120 activation-mediated action in obesity-related metabolic diseases and immune responses. In the past decade, there have been four agonists synthesized and characterized (see Table 1). GW9508, an agonist of GPR40, was the first to have reported that stimulates GPR120 receptor as well. Given no expression of GPR40 in monocytic RAW264.7 cells and macrophages, GW9508 was used to identify the physiological actions of GPR120. GW9508 inhibited LPS-induced phosphorylation of inflammatory signaling pathways and secretion of tumor necrosis factor-α. When GPR120 was knocked down or knocked out, the anti-inflammatory effects by GW9508 were abolished. In addition, GW9508 was reported to inhibit human eosinophil apoptosis by decreasing caspase-3 activity. Like GW9508, TUG-891 is an agonist of GPR40 as well as GPR120. In STC-1 cells, TUG-891 binds to GPR120 receptor, thus causing GPR120 internalization and triggering the release of GLP-1 (Hudson et al. 2013). Moreover, TUG-891-induced GPR120 activation mediated glucose uptake in 3T3-L1 adipocytes and TNF-α secretion in RAW264.7 cells. A selective agonist of GPR120, called compound A (cpdA), was recently developed to confirm the potential benefits of GPR120 in health (Oh et al. 2014). Interestingly, WT mice fed in HFD with cpdA supplement exhibited improved glucose tolerance, decreased hepatic steatosis, and increased insulin sensitivity. Meanwhile, the expression of pro-inflammatory genes and monocytic infiltration were decreased in adipose tissue of WT mice but not in those of GPR120 KO mice. In addition, cpdA-mediated GPR120 activation suppressed LPS-induced inflammation in macrophages. Another selective GPR120 agonist or a sulfonamide in nature, called GSK137647A (GSK), has also recently developed by GlaxoSmithKline. In this regard, it has been reported that GSK augmented insulin release from INS-1E cells and rat islets via calcium signaling; more interestingly, these insulinotropic effects of GSK-mediated GPR120 activation were enhanced in OND rat islets but decreased in diabetic rat islets (Zhang et al. 2016).

GPR120 Activation-Mediated Signaling Pathways

There are two main distinct signal transduction pathways of GPR120 actions in hormonal secretion and anti-inflammation (Fig. 2). As described, GPR120 is expressed in many endocrine cells involved in the regulation of hormonal secretion. In mouse intestinal cells, ligand-stimulated GPR120 binds to Gq/11 protein, and the complex activates phospholipase C (PLC); PLC is an enzyme which plays an important role in eukaryotic cell physiology. PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). On one hand, DAG activates protein kinase C (PKC) that induces ERK phosphorylation and thus suppresses ghrelin secretion. On the other hand, IP3 participates in the calcium (Ca2+) channels in the endoplasmic reticulum (ER), causing the increase of calcium in the cytosol, and thus triggers GLP-1 and CCK release; increases in GLP-1 levels enhance insulin secretion. Moreover, DHA and GSK also directly stimulate insulin release in pancreatic islets. TUG-891, a GPR120 agonist, was reported to increase glucose uptake in primary adipose tissue and 3T3-L1 adipocytes. GPR120-Gq/11 binding stimulates PI3K/Akt/GLUT4 signaling pathways and leads to the translocation of GLUT4 to the plasma membrane, thereby enhancing glucose intake in 3T3-L1 cells. All these demonstrated effects were blocked by Gq/11 knockdown. GPR120 was furthermore found to protect STC-1 cells against apoptosis and mediate pancreatic β-cell proliferation and 3T3 adipocyte differentiation (Oh et al. 2010; Ichimura et al. 2012).
GPR120, Fig. 2

Diagram of proposed pathways mediated by GPR120. PI3K, phosphoinositide 3-kinase; Akt, serine/threonine kinase also known as protein kinase B; GLUT4, glucose transporter type 4; PLC, phospholipase C; PIP2, phosphatidylinositol 4,5-bisphosphate; DAG, diacylglycerol; PKC, protein kinase C; ERK, extracellular signal-regulated kinases; IP3, 1,4,5-trisphosphate; Ca2+, calcium; β-arr2, β-arrestin-2; NLRP3, NACHT, LRR, and PYD domain-containing protein 3; IL-1β, interleukin 1 beta; LPS, lipopolysaccharides; Tnf-α, tumor necrosis factor alpha; TLR4, toll-like receptor 4; TNFR, Tnf-α receptor; TAK1, transforming growth factor-β-activated kinase 1; TAB1, TAK1 binding protein 1; NF-κB, nucleasr factor kappa B; JNK, c-Jun N-terminal kinase; AP-1, Activator protein 1; cox-2, cyclooxygenase-2; cxcl1, chemokine (C-X-C motif) ligand 1; ccl2, chemokine (C-C motif) ligand 2; il-6. interleukin 6

Pro-inflammatory inducers, such as LPS and Tnf-α, are widely used to induce responses in the inflammatory studies. LPS and Tnf-α bind to toll-like receptor 4 (TLR4) and Tnf-α receptor (TNFR), respectively; such binding leads to the interaction between transforming growth factor-β-activated kinase 1 (TAK1) and transforming growth factor-β-activated kinase 1 binding protein 1 (TAB1) to activate phosphorylation of nuclear factor NF-κB and c-Jun N-terminal kinase (JNK), which mediate downstream pro-inflammatory cascades. NF-κB and JNK phosphorylation promote the expression of various chemokines and cytokines, including cox-2, cxcl1, ccl2, tnf-α, il-1β, and il-6. These pro-inflammatory factors, in turn, initiate and intensify cell inflammatory events. Oh and co-workers had demonstrated that GPR120 stimulation by DHA, and GW9508 mediated anti-inflammatory effects in macrophages through the interaction with β-arrestin-2 (β-arr2) (Oh et al. 2014). In summary, GPR120 activation recruits β-arr2 and GPR120-β-arr2 complex internalizes; this complex interacts with TAB1, thereby blocking the association of TAB1 with TAK1 and inhibiting the subsequent inflammatory cascades. Furthermore, ω-3 FAs-mediated internalization of GPR120-β-arr2 also inhibits NLRP3 inflammasome activation and IL-1β release (Yan et al. 2013).

GPR120 in Health and Disease

Omega-3 fatty acids are well known to be essential for human health, which are commonly used as nutraceuticals because of the demonstrated benefits in diverse diseases. Solid evidence has documented that ω-3 FAs-induced GPR120 stimulation is protective against metabolic disorders and inflammation-driven disorders in both humans and animals. In fact, type 2 diabetes (T2D) is closely associated with obesity, and considerable studies suggest a negative correlation between obesity and GPR120. In humans, GPR120 mutation increases the risk of obesity, while similar results were also observed in GPR120-deficient mice (Ichimura et al. 2012). GPR120 functions as an anti-obesity target for regulating appetite, body weight, and hormonal secretion; the latter includes GLP-1, CCK, ghrelin, somatostatin, glucagon, and insulin; these hormones, in turn, have positive effects on insulin sensitivity, glucose metabolism, and whole-body homeostasis. In light of these findings, GPR120 has a potential therapeutic target for obesity and T2D. Chronic inflammation plays a critical role for the development of insulin resistance in obesity. It was reported that GPR120 activation not only inhibited macrophage-driven inflammation but also suppressed NLRP3 inflammasome-dependent inflammation in high-fat-diet-induced mice (Yan et al. 2013). GPR120-mediated anti-inflammatory effects contribute, at least partially, to the improvement of glucose tolerance and insulin sensitivity in obese mice (Oh et al. 2014). In view of this evidence, it prompts us to speculate that GPR120 is an emerging candidate target for the management of obesity and obesity-related metabolic diseases as well as inflammation-relevant disorders.


GPR120, being the receptor of ω-3 FAs, has garnered considerable attention because of its regulatory actions in hormonal secretion and anti-inflammation in human diseases. Accumulated evidence has consolidated that GPR120 activation with natural ligands or synthetic agonists enhances the release of incretin hormones GLP-1 and CCK that have profound effects on our bodily metabolism. The endocrine roles of GPR120 are mainly achieved by its coupling to the Gα-protein-mediated downstream signaling pathways, such as PI3K/Akt signal cascades, as well as by eliciting the calcium signaling. The identification of GPR120-mediated anti-inflammatory and insulin-sensitizing effects on macrophage and adipocytes points to GPR120 agonism to be a potential therapeutic for obesity and obesity-associated metabolic diseases; however, the selectivity of currently available agonists of GPR120 over GPR40 is suboptimal so that more selective small molecules for GPR120 activation warrant to be designed and developed for its clinical application in the future.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.School of Biomedical Sciences, Faculty of MedicineThe Chinese University of Hong KongShatin, New TerritoriesChina