title: The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms.
abstract: The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Center Munich and Division of Metabolic Diseases, Department of Medicine, Technical University Munich, Munich, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Habegger
authors.forename: Carola W
authors.initials: CW
authors.lastname: Meyer
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gaylinn
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.forename: Kristy
authors.initials: K
authors.lastname: Heppner
authors.forename: Chitrang
authors.initials: C
authors.lastname: Trivedi
authors.forename: Maximilian
authors.initials: M
authors.lastname: Bielohuby
authors.forename: William
authors.initials: W
authors.lastname: Abplanalp
authors.forename: Franziska
authors.initials: F
authors.lastname: Meyer
authors.forename: Carolin L
authors.initials: CL
authors.lastname: Piechowski
authors.forename: Juliane
authors.initials: J
authors.lastname: Pratzka
authors.forename: Kerstin
authors.initials: K
authors.lastname: Stemmer
authors.forename: Jenna
authors.initials: J
authors.lastname: Holland
authors.forename: Jazzmin
authors.initials: J
authors.lastname: Hembree
authors.forename: Nakul
authors.initials: N
authors.lastname: Bhardwaj
authors.forename: Christine
authors.initials: C
authors.lastname: Raver
authors.forename: Nickki
authors.initials: N
authors.lastname: Ottaway
authors.forename: Radha
authors.initials: R
authors.lastname: Krishna
authors.forename: Renu
authors.initials: R
authors.lastname: Sah
authors.forename: Floyd R
authors.initials: FR
authors.lastname: Sallee
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: Diego
authors.initials: D
authors.lastname: Perez-Tilve
authors.forename: Martin
authors.initials: M
authors.lastname: Bidlingmaier
authors.forename: Michael O
authors.initials: MO
authors.lastname: Thorner
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.forename: David
authors.initials: D
authors.lastname: Smiley
authors.forename: Richard
authors.initials: R
authors.lastname: DiMarchi
authors.forename: Susanna
authors.initials: S
authors.lastname: Hofmann
authors.forename: Paul T
authors.initials: PT
authors.lastname: Pfluger
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects; D020869:Gene Expression Profiling; D054439:Ghrelin / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism; D010641:Phenotype; D055503:Protein Multimerization / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D044104:Receptor, Melanocortin, Type 3 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D054440:Receptors, Ghrelin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D054369:Agouti-Related Protein; D054439:Ghrelin; C501984:Gpr83 protein, mouse; C505392:MC3R protein, human; D044104:Receptor, Melanocortin, Type 3; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin