Abstract
GPR40/FFAR1 is a Gq protein-coupled receptor expressed in pancreatic β cells and enteroendocrine cells, and mediates insulin and incretin secretion to regulate feeding behavior. Several GPR40 full agonists have been reported to reduce food intake in rodents by regulating gut hormone secretion in addition to their potent glucose-lowering effects; however, detailed mechanisms of feeding suppression are still unknown. In the present study, we characterized T-3601386, a novel compound with potent full agonistic activity for GPR40, by using in vitro Ca2+ mobilization assay in Chinese hamster ovary (CHO) cells expressing FFAR1 and in vivo hormone secretion assay. We also evaluated feeding suppression and weight loss after the administration of T-3601386 and investigated the involvement of the vagal nerve in these effects. T-3601386, but not a partial agonist fasiglifam, increased intracellular Ca2+ levels in CHO cells with low FFAR1 expression, and single dosing of T-3601386 in diet-induced obese (DIO) rats elevated plasma incretin levels, suggesting full agonistic properties of T-3601386 against GPR40. Multiple doses of T-3601386, but not fasiglifam, in DIO rats showed dose-dependent weight loss accompanied by feeding suppression and durable glucagon-like peptide-1 elevation, all of which were completely abolished in Ffar1-/- mice. Immunohistochemical analysis in the nuclei of the solitary tract demonstrated that T-3601386 increased the number of c-Fos positive cells, which also disappeared in Ffar1-/- mice. Surgical vagotomy and drug-induced deafferentation counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386 exerts incretin release and weight loss in a GPR40-dependent manner, and that afferent vagal nerves are important for the feeding suppression induced by GPR40 full agonism. Our novel findings raise the possibility that GPR40 full agonist can induce periphery-derived weight reduction, which may provide benefits such as less adverse effects in central nervous system compared to centrally-acting anti-obesity drugs.
Highlights
Impaired insulin secretion from pancreatic β cells and peripheral insulin resistance are common characteristics observed in patients with type 2 diabetes [1]
We tested in vivo incretin secretion and clear increases in plasma levels of total GLP-1 and GIP were observed after oral dose of T3601386 (10 and 30 mg/kg) in diet-induced obese (DIO)-F344 rats (Fig 2A–2D)
We showed that T-3601386 clearly reduces food intake and body weight (BW) accompanied by incretin secretion via GPR40
Summary
Impaired insulin secretion from pancreatic β cells and peripheral insulin resistance are common characteristics observed in patients with type 2 diabetes [1]. GPR40/FFAR1 is a member of the 7-transmenbrane G protein-coupled receptors (GPCR), and medium- to long-chain fatty acids have been identified as its endogenous ligands [5, 6]. It is highly expressed in pancreatic β cells and agonist stimulation leads to elevations in intracellular Ca2+ levels followed by glucose-dependent insulin secretion [7, 8]. Et al recently reported GPR40 agonist-induced suppression of food intake and BW [20] Their results demonstrated that GLP-1 receptor (GLP1R) as well as GPR40 contributed to the agonist-mediated feeding suppression; detailed analysis of its action site has not been carried out
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