GPR120

Official Full Name

free fatty acid receptor 4

Organism

Homo sapiens

GeneID

338557

Background

This gene encodes a G protein-coupled receptor (GPR) which belongs to the rhodopsin family of GPRs. The encoded protein functions as a receptor for free fatty acids, including omega-3, and participates in suppressing anti-inflammatory responses and insulin sensitizing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2012]

Synonyms

FFAR4; GT01; PGR4; OB10Q; BMIQ10; GPR120; GPR129; O3FAR1;

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Detailed Information

Omega-3 fatty acids are found to beneficially influence the development of metabolic syndrome and type 2 diabetes. The G protein-coupled 7-transmembrane domain receptor GPR120 is abundantly expressed in lung, intestines, adipose tissue, and proinflammatory macrophages and is activated by long-chain free fatty acids (FFAs), in particular ω-3 polyunsaturated FFAs such as eicosapentaenoic acid (EPA), α-linolenic acid, and docosahexaenoic acid (DHA). The receptor has been reported to mediate FFA promoted the release of glucagon-like peptide-1 (GLP-1), an incretin hormone that increases glucose-stimulated insulin secretion, insulin sensitivity, and β-cell mass and reduces appetite and gastric emptying.

Binding of GPR120 by ω-3 fatty acids (ω-3 FAs) leads to various physiological activities that have a stabilizing effect on metabolic homeostasis and may help prevent diabetes. Patients with T2DM exhibit insufficient pancreatic insulin secretion and insulin resistance in liver, adipose, and muscle; insulin resistance correlates with abnormal energy metabolism, such as a sequela of hepatic steatosis. GPR120 activation relieves insulin resistance via enabling adipogenesis in adipose tissue and thereby maintaining a lipid metabolism balance between adipose and liver tissues. In addition, GPR120 stimulation can also support maintenance of insulin sensitivity through inhibition of inflammation, because GPR120 plays a crucial role in mediating the anti-inflammatory effects of ω-3 FAs on macrophages. GPR120 activation may also promote pancreatic β-cell survival and proliferation and stimulate pancreatic insulin secretion indirectly by induction of glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) secretion from the intestine. In general, GPR120-mediated modulation on insulin sensitivity, pancreatic insulin secretion, and β-cell mass shows that GPR120 could be targeted as an anti-diabetic treatment.

Figure 1. GPR120 is an ω-3 FA receptor/sensor, and loss of function leads to obesity and insulin resistance

When stimulated by extracellular ω-3 FA ligands, GPR120 on the cell surface can be phosphorylated by kinases, resulting in the increase in affinity of GPR120 intracellular domain to scaffold protein β-arrestin-2. Once GPR120 is bound to β-arrestin-2, the G-protein coupling to GPR120 is prevented, and then GPR120-β-arrestin-2 complex is internalized to the cytoplasm where downstream signaling can proceed. So far, all anti-inflammatory effects of GPR120 ligands on macrophages appear to be mediated by GPR120–β-arrestin-2 signaling. The activation of this signaling can inhibit production of pro-inflammatory factors – such as cyclooxygenase-2 (COX-2), monocyte chemotactic protein-1 (MCP-1), interleukin (IL)-18, and IL-1β – by binding TAB1 (transforming growth factor-β activated kinase 1 [TAK1]-binding protein 1) or an inflammasome known as nucleotide-binding oligomerization leucine-rich repeat and pyrin domain-containing protein (NLRP)3/1b.

The drug discovery arena for new anti-diabetic drugs is highly competitive and a number of pharmaceutical companies and academic institutes are actively engaged in this area and filing a number of patents. A paradigm shift in the treatment of diabetes is needed, wherein a single therapeutic agent could target diabetes and its associated disorders with excellent safety and tolerability profile. In this regard, agonists of GPR120 are highly anticipated as therapeutic methods for treatment of diabetes on the basis of their novel glucose-dependent mechanism of action. Besides, GPR120 is highly expressed in macrophages and adipocytes, and activation of GPR120 inhibits toll-like receptor 4 (TLR4)- and TNFR-mediated inflammation by β-arrestin-2 and blocks the inflammation pathway. Therefore, diseases mediated by one or any of these pathways can be targeted via GPR120.

References:

Shimpukade B, et al. Discovery of a Potent and Selective GPR120 Agonist. Journal of Medicinal Chemistry, 2012, 55(9):4511-4515.
Oh D, Olefsky J. Omega 3 Fatty Acids and GPR120. Cell Metabolism, 2012, 15(5):0-565.
Sing L P, Dan Z. Potential roles of GPR120 and its agonists in the management of diabetes. Drug Design, Development and Therapy, 2014:1013-.
Halder S, et al. The therapeutic potential of GPR120: a patent review. Expert Opinion on Therapeutic Patents, 2013, 23(12):1581-1590.

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