title: GPR119, a Major Enteroendocrine Sensor of Dietary Triglyceride Metabolites Coacting in Synergy With FFA1 (GPR40).
abstract: Triglycerides (TGs) are among the most efficacious stimulators of incretin secretion; however, the relative importance of FFA1 (G Protein-coupled Receptor [GPR] 40), FFA4 (GPR120), and GPR119, which all recognize TG metabolites, ie, long-chain fatty acid and 2-monoacylglycerol, respectively, is still unclear. Here, we find all 3 receptors to be highly expressed and highly enriched in fluorescence-activated cell sorting-purified GLP-1 and GIP cells isolated from transgenic reporter mice. In vivo, the TG-induced increase in plasma GIP was significantly reduced in FFA1-deficient mice (to 34%, mean of 4 experiments each with 8-10 animals), in GPR119-deficient mice (to 24%) and in FFA1/FFA4 double deficient mice (to 15%) but not in FFA4-deficient mice. The TG-induced increase in plasma GLP-1 was only significantly reduced in the GPR119-deficient and the FFA1/FFA4 double deficient mice, but not in the FFA1, and FFA4-deficient mice. In mouse colonic crypt cultures the synthetic FFA1 agonists, TAK-875 stimulated GLP-1 secretion to a similar extent as the prototype GLP-1 secretagogue neuromedin C; this, however, only corresponded to approximately half the maximal efficiency of the GPR119 agonist AR231453, whereas the GPR120 agonist Metabolex-209 had no effect. Importantly, when the FFA1 agonist was administered on top of appropriately low doses of the GPR119 agonist, a clear synergistic, ie, more than additive, effect was observed. It is concluded that the 2-monoacylglycerol receptor GPR119 is at least as important as the long-chain fatty acid receptor FFA1 in mediating the TG-induced secretion of incretins and that the 2 receptors act in synergy, whereas FFA4 plays a minor if any role.
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Jeppe H
authors: JH
authors: Ekberg
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Maria
authors: M
authors: Hauge
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Line V
authors: LV
authors: Kristensen
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Andreas N
authors: AN
authors: Madsen
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Maja S
authors: MS
authors: Engelstoft
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Anna-Sofie
authors: AS
authors: Husted
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Rasmus
authors: R
authors: Sichlau
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Kristoffer L
authors: KL
authors: Egerod
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Pascal
authors: P
authors: Timshel
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Timothy J
authors: TJ
authors: Kowalski
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Fiona M
authors: FM
authors: Gribble
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Frank
authors: F
authors: Reiman
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Harald S
authors: HS
authors: Hansen
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Andrew D
authors: AD
authors: Howard
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Birgitte
authors: B
authors: Holst
authors: NNF Center for Basic Metabolic Research (J.H.E., M.H., L.V.K., A.N.M., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Section for Metabolic Receptology; Laboratory for Molecular Pharmacology (J.H.E., M.H., L.V.K., M.S.E., A.-S.H., R.S., K.L.E., B.H., T.W.S.), Department of Neuroscience and Pharmacology; and Danish Diabetes Academy (M.S.E.), 5000 Odense, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research (P.T.), Section for Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Merck Research Laboratories (T.J.K., A.D.H.), Kenilworth, New Jersey 07033; Cambridge Institute for Medical Research and MRC Metabolic Diseases Unit (F.M.G., F.R.), University of Cambridge, Cambridge, CB20QQ United Kingdom; Department of Drug Design and Pharmacology (H.S.H.), University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors: Thue W
authors: TW
authors: Schwartz
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D001839:Bombesin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D004041:Dietary Fats; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001572:Benzofurans; D004041:Dietary Fats; C498007:FFAR4 protein, mouse; C473036:Ffar1 protein, mouse; C516207:Gpr119 protein, mouse; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875; D014280:Triglycerides; C040794:neuromedin C; D052216:Glucagon-Like Peptide 1; D001839:Bombesin