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Pharmacological Evaluation of GPR40 Full Agonists in Metabolic Disease Models

上野, 光 筑波大学 DOI:10.15068/0002000834

2021.08.02

概要

GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells, and its stimulation enhances insulin and incretin secretion. Since these hormones contribute to glycemic control and feeding regulation, GPR40 agonists have a potential to become a novel agent for the treatment of diabetes and obesity. Here, I report the pharmacological profiles of SCO-267, a newly-synthesized GPR40 full agonist. In addition, I introduce the contribution of afferent vagal nerves regarding GPR40 full agonism-derived feeding suppression, detailed mechanisms of which are still unknown.

In the first chapter, I conducted the in vitro/in vivo characterization of SCO-267. SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing Chinese hamster ovary (CHO) cells, stimulated insulin secretion in MIN6 cells, and induced glucagon-like peptide-1 (GLP-1) release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic polypeptide, and peptide YY secretions. In single and 2-week dosing studies using diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance with lower plasma exposure compared with fasiglifam, a partial agonist. Diet-induced obese (DIO) rats treated with SCO-267 for 2 weeks decreased food intake and body weight. These results show the full agonistic property of SCO-267 against GPR40 and suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

In the second chapter, I tried a mechanism analysis of GPR40-mediated feeding suppression using T-3601386, another compound with potent full agonistic activity for GPR40. As was the case with SCO-267, T-3601386 showed Ca2+ mobilization in FFAR1- expressing CHO cells, in vitro/in vivo GLP-1 secretory capacity and body weight reduction in DIO rats, indicating full agonistic properties of T-3601386 against GPR40. Immunohistochemical analysis demonstrated that T-3601386 increased the number of c- Fos positive cells in the nuclei of the solitary tract (NTS), which receives vagally- mediated signals. Incretin secretion, feeding suppression, weight loss and NTS activation induced by T-3601386 were completely abolished in Ffar1-/- mice. Two models with vagal nerve blockade counteracted the feeding suppression and weight loss induced by the administration of T-3601386. These results suggest that T-3601386-induced feeding suppression and NTS activation is dependent on GPR40, and that intact vagal afferents are required for the feeding suppression through GPR40.

In conclusion, SCO-267 is highly effective in improving diabetes and obesity and may induce similar favorable effects in patients with metabolic disease. Moreover, my 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.

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