title: The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo.
abstract: The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function. Here we show that the receptor is also diffusely expressed in cells of the gastrointestinal system, from stomach to descending colon. Furthermore, MC4R is the second most highly enriched GPCR in peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) expressing enteroendocrine L cells. When vectorial ion transport is measured across mouse or human intestinal mucosa, administration of α-MSH induces a MC4R-specific PYY-dependent antisecretory response consistent with a role for the MC4R in paracrine inhibition of electrolyte secretion. Finally, MC4R-dependent acute PYY and GLP-1 release from L cells can be stimulated in vivo by intraperitoneal (i.p.) administration of melanocortin peptides to mice. This suggests physiological significance for MC4R in L cells and indicates a previously unrecognized peripheral role for the MC4R, complementing vagal and central receptor functions.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Brandon L
authors.initials: BL
authors.lastname: Panaro
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Tough
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Danish Diabetes Academy, 5000 Odense, Denmark.
authors.forename: Maja S
authors.initials: MS
authors.lastname: Engelstoft
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Matthews
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Digby
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Diabetes and Obesity Biology, Novo Nordisk A/S, 2760 Maaloev, Denmark.
authors.forename: Cathrine L
authors.initials: CL
authors.lastname: Møller
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, 2200 Denmark.
authors.forename: Berit
authors.initials: B
authors.lastname: Svendsen
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research (CIMR) & MRC Metabolic Diseases Unit (MDU), Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Gribble
authors.affiliation: University of Cambridge, Cambridge Institute for Medical Research (CIMR) & MRC Metabolic Diseases Unit (MDU), Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Danish Diabetes Academy, 5000 Odense, Denmark.
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.affiliation: Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark; Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Medical and Health Sciences, University of Copenhagen, 2200 Denmark.
authors.forename: Thue W
authors.initials: TW
authors.lastname: Schwartz
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Cox
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: roger.cone@vanderbilt.edu.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cone
mesh_terms: D000147:Acids, Heterocyclic / Q000494:pharmacology; D000818:Animals; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019858:Enteroendocrine Cells / Q000187:drug effects / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010069:Oxadiazoles / Q000494:pharmacology; D019894:Peptide YY / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists / Q000378:metabolism*
chemical_list: D000147:Acids, Heterocyclic; C116941:HS014 cyclic peptide; D010069:Oxadiazoles; C534146:PSN 632408; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1