title: GPR40 reduces food intake and body weight through GLP-1.
abstract: G protein-coupled receptor 40 (GPR40) partial agonists lower glucose through the potentiation of glucose-stimulated insulin secretion, which is believed to provide significant glucose lowering without the weight gain or hypoglycemic risk associated with exogenous insulin or glucose-independent insulin secretagogues. The class of small-molecule GPR40 modulators, known as AgoPAMs (agonist also capable of acting as positive allosteric modulators), differentiate from partial agonists, binding to a distinct site and functioning as full agonists to stimulate the secretion of both insulin and glucagon-like peptide-1 (GLP-1). Here we show that GPR40 AgoPAMs significantly increase active GLP-1 levels and reduce acute and chronic food intake and body weight in diet-induced obese (DIO) mice. These effects of AgoPAM treatment on food intake are novel and required both GPR40 and GLP-1 receptor signaling pathways, as demonstrated in GPR40 and GLP-1 receptor-null mice. Furthermore, weight loss associated with GPR40 AgoPAMs was accompanied by a significant reduction in gastric motility in these DIO mice. Chronic treatment with a GPR40 AgoPAM, in combination with a dipeptidyl peptidase IV inhibitor, synergistically decreased food intake and body weight in the mouse. The effect of GPR40 AgoPAMs on GLP-1 secretion was recapitulated in lean, healthy rhesus macaque demonstrating that the putative mechanism mediating weight loss translates to higher species. Together, our data indicate effects of AgoPAMs that go beyond glucose lowering previously observed with GPR40 partial agonist treatment with additional potential for weight loss.
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Gorski
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Michele J
authors.initials: MJ
authors.lastname: Pachanski
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Joel
authors.initials: J
authors.lastname: Mane
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Plummer
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Sarah
authors.initials: S
authors.lastname: Souza
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Brande S
authors.initials: BS
authors.lastname: Thomas-Fowlkes
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Aimie M
authors.initials: AM
authors.lastname: Ogawa
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Weinglass
authors.affiliation: Department of In Vitro Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey; and.
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Boonlert
authors.initials: B
authors.lastname: Cheewatrakoolpong
authors.affiliation: Department of Cardiometabolic Diseases, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, New Jersey.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti
authors.affiliation: Department of In Vivo Pharmacology, Merck Research Laboratories, Kenilworth, New Jersey; maria_trujillo@merck.com.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Trujillo
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000235:genetics*; D001835:Body Weight / Q000235:genetics*; D004435:Eating / Q000235:genetics*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015431:Weight Loss / Q000502:physiology*
chemical_list: C473036:Ffar1 protein, mouse; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1
keywords: G protein-coupled receptor 40; diabetes; diet-induced obesity; glucagon-like peptide-1; obesity