GPR40 full agonism exerts feeding suppression and weight loss through afferent vagal nerve
Autoři:
Hikaru Ueno aff001; Ryo Ito aff001; Shin-ichi Abe aff001; Hitomi Ogino aff001; Minoru Maruyama aff001; Hirohisa Miyashita aff001; Yasufumi Miyamoto aff001; Yusuke Moritoh aff002; Yoshiyuki Tsujihata aff001; Koji Takeuchi aff001; Nobuhiro Nishigaki aff001
Působiště autorů:
Cardiovascular Metabolic Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
aff001; Research and Development Division, SCOHIA PHARMA Inc., Kanagawa, Japan
aff002
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0222653
Souhrn
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.
Klíčová slova:
Medicine and health sciences – Pharmaceutics – Drug therapy – Drug administration – Anesthesia – Local and regional anesthesia – Nerve block – Anesthesiology – Body weight – Weight loss – Surgical and invasive medical procedures – Nervous system procedures – Vagotomy – Endocrinology – Diabetic endocrinology – Insulin – Biology and life sciences – Physiology – Physiological processes – Secretion – Food consumption – Physiological parameters – Biochemistry – Hormones – Research and analysis methods – Biological cultures – Cell lines – CHO cells
Zdroje
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