Cloning and characterization of the rat free fatty acid receptor GPR120: in vivo effect of the natural ligand on GLP-1 secretion and proliferation of pancreatic β cells

Abstract

We have recently found that GPR120, which is abundantly expressed in intestine, functions as a receptor for unsaturated long-chain free fatty acids (FFAs) and that GPR120 stimulation promotes the secretion of glucagons-like peptide-1 (GLP-1) in the mouse (Hirasawa et al., Nat Med 11:90-94, 2005). In this study, we cloned and characterized rat GPR120 (rGPR120), and then we examined the in vivo effects of acute and long-term administration of the natural ligand alpha-linolenic acid (alpha-LA). The cloned rat GPR120 complimentary DNA had a seven transmembrane structure, and a homology comparison of human, mouse, and rat GPR120 revealed that the rat GPR120 (rGPR120) shares 85 and 98% sequence identity with the human and mouse GPR120 proteins, respectively. The tissue distribution and ligand properties of rGPR120 were similar to those of mouse GPR120. In addition, alpha-LA provoked a transient increase in [Ca2+]i levels in HEK293 cells expressing rGPR120. Furthermore, administration of alpha-LA to the rat increased plasma GLP-1 levels, and long-term administration of alpha-LA led to proliferation of pancreatic beta cells, probably because of the enhanced GLP-1 secretion. These results show that rat GPR120 is a G-protein-coupled receptor whose ligand is a free fatty acid, and it may play an important role in the FFA-associated physiological responses.

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

“…Furthermore, it is also evident that any effects of orally administered GPR120 agonists on insulin secretion are likely to be mediated mainly by indirect actions on the intestine. This is because GPR120 is expressed on intestinal enteroendocrine cells where it regulates the secretion of incretins such as GIP, GLP-1 and cholecystokinin [130][131][132][133][134]. Therefore, on the basis of these considerations, it seems unlikely that GPR120 plays any direct role in regulating insulin secretion.…”

“…GPR40 is abundantly expressed in pancreatic β-cells (see below) but GPR41 may be predominantly localised on immune cells [18] and GPR43 on adipocytes [19]. In addition to these molecules, certain structurally more divergent receptors whose ligands are free or derivatised fatty acids are encoded elsewhere in the genome, including GPR84, GPR119 and GPR120 [20][21][22].…”

Differential Signaling by Splice Variants of the Human Free Fatty Acid Receptor GPR120

“…This receptor is a nutrient sensor on colonic L-type enteroendocrine cells, where its stimulation by luminal FFAs releases incretins such as glucagon-like peptide-1 and cholecystokinin into the circulation (Hirasawa et al, 2005;Tanaka et al, 2008), indirectly leading to increased insulin secretion. FFA1, which is coexpressed in similar cells, may contribute to these effects (Edfalk et al, 2008), and both FFA1 and GPR120 also act as FFA detectors in taste buds (Cartoni et al, 2010).…”

“…Investigations of GPR120L pharmacology have in general required overexpression of promiscuous or chimeric G␣ subunits (Hirasawa et al, 2005;Galindo et al, 2012). In the absence of this method of facilitating G protein coupling, most recent studies have focused on human and rodent equivalents of GPR120S (Tanaka et al, 2008;Moore et al, 2009;Oh et al, 2010;Galindo et al, 2012).…”

How reliable are G-protein-coupled receptor antibodies?

“…for nociceptin/orphanin FQ receptors (Ibba et al 2008), suitable radioligands are missing for many other GPCR, e.g. for β 3 -adrenoceptors (Vrydag and Michel 2007) or free fatty acid receptors (Tanaka et al 2008). Therefore, antibodies are the only available option to detect many GPCR, and numerous such antibodies are commercially available from various suppliers.…”