GPR119, a novel G protein‐coupled receptor target for the treatment of type 2 diabetes and obesity

Abstract

GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (b-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G as coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic b-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed.

A single-cell survey of the small intestinal epithelium

“…These included many nutrient-sensing receptors ( e.g. , Gpbar1 -a, a bile acid receptor 20 , and Gpr119 , a sensor for food intake and glucose homeostasis 21 ) in enteroendocrine cells, and Drd3 , a dopamine receptor in tuft cells (Extended Data Fig. 2d).…”

“…For example, we provide a detailed profile of the GPCRs expressed by IECs, including EEC subsets. Notably, the important cannabinoid receptor Gpr119 21 was enriched in the novel SILA subset (FDR < 0.05, Extended Data Fig. 6d), which co-expresses Ghrl and Gcg , genes encoding gut hormones that regulate appetite and satiety.…”

“…These receptors are known to induce the expression of GIP and Gcg to maintain energy homeostasis 1 . Ffar2 was expressed by some progenitors and by EC cells, but notably absent from GIP-expressing cells, while the oleoylethanolamide receptor Gpr119, important for food intake and glucose homeostasis 2 , is expressed highest in SILA cells.…”

G-protein coupled receptors mediating long chain fatty acid signalling in the pancreatic beta-cell

“…Ectopic expression of GPR119 in various easily transfected cell lines has yielded unanimous support for the view that activation of the receptor is associated with a rise in cAMP levels [101][102][103][104]. Moeover, exposure of cultured β-cells to GPR119 ligands also elicits a rise in cAMP; as does treatment of the intestinal Lcell line, GLUTag [105].…”

Seven Transmembrane-spanning Receptors for Free Fatty Acids as Therapeutic Targets for Diabetes Mellitus: Pharmacological, Phylogenetic, and Drug Discovery Aspects

“…GPR119 is significantly enriched in human pancreatic and gastrointestinal tissue (13); it is expressed mainly in ␤-cells of isolated pancreatic islets from mice (14). GPR120 is abundantly expressed in the intestine but is not expressed in the pancreas or clonal ␤-cells (5).…”