title: Hypothalamic POMC neurons promote cannabinoid-induced feeding.
abstract: Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide α-melanocyte-stimulating hormone, and the opioid peptide β-endorphin. CB1R activation selectively increases β-endorphin but not α-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.
authors.affiliation: 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Koch
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Varela
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Jae Geun
authors.initials: JG
authors.lastname: Kim
authors.affiliation: 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Jung Dae
authors.initials: JD
authors.lastname: Kim
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernández-Nuño
authors.affiliation: Obesity &Diabetes Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Simonds
authors.affiliation: Division of Endocrinology &Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Castorena
authors.affiliation: Division of Endocrinology &Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Vianna
authors.affiliation: Division of Endocrinology &Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Yury M
authors.initials: YM
authors.lastname: Morozov
authors.affiliation: 1] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Pasko
authors.initials: P
authors.lastname: Rakic
authors.affiliation: Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Bechmann
authors.affiliation: Obesity &Diabetes Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cowley
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Klara
authors.initials: K
authors.lastname: Szigeti-Buck
authors.affiliation: 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Marcelo O
authors.initials: MO
authors.lastname: Dietrich
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Gao
authors.affiliation: 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Diano
authors.affiliation: 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Tamas L
authors.initials: TL
authors.lastname: Horvath
mesh_terms: D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects* / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects; D007031:Hypothalamus / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D012528:Satiety Response / Q000187:drug effects / Q000502:physiology; D000071246:Uncoupling Protein 2; D000521:alpha-MSH / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: D002186:Cannabinoids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D043884:Receptor, Cannabinoid, CB1; D000071246:Uncoupling Protein 2; D009270:Naloxone; D000521:alpha-MSH; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin