title: GPR119 is required for physiological regulation of glucagon-like peptide-1 secretion but not for metabolic homeostasis.
abstract: G protein-coupled receptor 119 (GPR119) is expressed in pancreatic islets and intestine, and is involved in insulin and incretin hormone release. GPR119-knockout (Gpr119(-/-)) mice were reported to have normal islet morphology and normal size, body weight (BW), and fed/fasted glucose levels. However, the physiological function of GPR119 and its role in maintaining glucose homeostasis under metabolic stress remain unknown. Here, we report the phenotypes of an independently generated line of Gpr119(-/-) mice under basal and high-fat diet (HFD)-induced obesity. Under low-fat diet feeding, Gpr119(-/-) mice show normal plasma glucose and lipids, but have lower BWs and lower post-prandial levels of active glucagon-like peptide 1 (GLP-1). Nutrient-stimulated GLP-1 release is attenuated in Gpr119(-/-) mice, suggesting that GPR119 plays a role in physiological regulation of GLP-1 secretion. Under HFD-feeding, both Gpr119(+)(/)(+) and Gpr119(-/-) mice gain weight similarly, develop hyperinsulinemia and hyperleptinemia, but not hyperglycemia or dyslipidemia. Glucose and insulin tolerance tests did not reveal a genotypic difference. These data show that GPR119 is not essential for the maintenance of glucose homeostasis. Moreover, we found that oleoylethanolamide (OEA), reported as a ligand for GPR119, was able to suppress food intake in both Gpr119(+)(/)(+) and Gpr119(-/-) mice, indicating that GPR119 is not required for the hypophagic effect of OEA. Our results demonstrate that GPR119 is important for incretin and insulin secretion, but not for appetite suppression.
authors.affiliation: Department of Cardiovascular and Metabolic Disease Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. hong.lan@spcorp.com
authors.forename: Hong
authors.initials: H
authors.lastname: Lan
authors.forename: Galya
authors.initials: G
authors.lastname: Vassileva
authors.forename: Aaron
authors.initials: A
authors.lastname: Corona
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Hana
authors.initials: H
authors.lastname: Baker
authors.forename: Andrei
authors.initials: A
authors.lastname: Golovko
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Abbondanzo
authors.forename: Weiwen
authors.initials: W
authors.lastname: Hu
authors.forename: Shijun
authors.initials: S
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Ning
authors.forename: Robert A
authors.initials: RA
authors.lastname: Del Vecchio
authors.forename: Frederique
authors.initials: F
authors.lastname: Poulet
authors.forename: Maureen
authors.initials: M
authors.lastname: Laverty
authors.forename: Eric L
authors.initials: EL
authors.lastname: Gustafson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hedrick
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kowalski
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D063388:Endocannabinoids; D005260:Female; D018390:Gene Targeting; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics*; D054795:Incretins / Q000378:metabolism / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008244:Lysophosphatidylcholines / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009829:Oleic Acids / Q000378:metabolism / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D055571:Secretory Pathway / Q000187:drug effects / Q000235:genetics*
chemical_list: D063388:Endocannabinoids; C516207:Gpr119 protein, mouse; D054795:Incretins; D008244:Lysophosphatidylcholines; D009829:Oleic Acids; D043562:Receptors, G-Protein-Coupled; C488250:oleoylethanolamide; D052216:Glucagon-Like Peptide 1; D005947:Glucose