title: Hypothalamic kappa opioid receptor mediates both diet-induced and melanin concentrating hormone-induced liver damage through inflammation and endoplasmic reticulum stress.
abstract: The opioid system is widely known to modulate the brain reward system and thus affect the behavior of humans and other animals, including feeding. We hypothesized that the hypothalamic opioid system might also control energy metabolism in peripheral tissues. Mice lacking the kappa opioid receptor (κOR) and adenoviral vectors overexpressing or silencing κOR were stereotaxically delivered in the lateral hypothalamic area (LHA) of rats. Vagal denervation was performed to assess its effect on liver metabolism. Endoplasmic reticulum (ER) stress was inhibited by pharmacological (tauroursodeoxycholic acid) and genetic (overexpression of the chaperone glucose-regulated protein 78 kDa) approaches. The peripheral effects on lipid metabolism were assessed by histological techniques and western blot. We show that in the LHA κOR directly controls hepatic lipid metabolism through the parasympathetic nervous system, independent of changes in food intake and body weight. κOR colocalizes with melanin concentrating hormone receptor 1 (MCH-R1) in the LHA, and genetic disruption of κOR reduced melanin concentrating hormone-induced liver steatosis. The functional relevance of these findings was given by the fact that silencing of κOR in the LHA attenuated both methionine choline-deficient, diet-induced and choline-deficient, high-fat diet-induced ER stress, inflammation, steatohepatitis, and fibrosis, whereas overexpression of κOR in this area promoted liver steatosis. Overexpression of glucose-regulated protein 78 kDa in the liver abolished hypothalamic κOR-induced steatosis by reducing hepatic ER stress.
  
  
  
  This study reveals a novel hypothalamic-parasympathetic circuit modulating hepatic function through inflammation and ER stress independent of changes in food intake or body weight; these findings might have implications for the clinical use of opioid receptor antagonists. (Hepatology 2016;64:1086-1104).
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Imbernon
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Estrella
authors.initials: E
authors.lastname: Sanchez-Rebordelo
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Romero-Picó
authors.affiliation: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Imre
authors.initials: I
authors.lastname: Kalló
authors.affiliation: Division of Endocrinology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Chee
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: Porteiro
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Omar
authors.initials: O
authors.lastname: Al-Massadi
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Contreras
authors.affiliation: Department of Clinical Science, KG Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
authors.forename: Johan
authors.initials: J
authors.lastname: Fernø
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Senra
authors.affiliation: Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Gallego
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.|Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo, Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
authors.forename: Cintia
authors.initials: C
authors.lastname: Folgueira
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.|Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo, Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Seoane
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Margriet
authors.initials: M
authors.lastname: van Gestel
authors.affiliation: Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Adan
authors.affiliation: Laboratory of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Liposits
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Dieguez
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria. ruben.nogueiras@usc.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain. ruben.nogueiras@usc.es.
authors.forename: Ruben
authors.initials: R
authors.lastname: Nogueiras
mesh_terms: D000818:Animals; D004032:Diet; D059865:Endoplasmic Reticulum Stress; D007028:Hypothalamic Hormones / Q000502:physiology*; D007031:Hypothalamus / Q000502:physiology*; D007249:Inflammation / Q000150:complications / Q000209:etiology; D008107:Liver Diseases / Q000209:etiology*; D008543:Melanins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010907:Pituitary Hormones / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000502:physiology*
chemical_list: D007028:Hypothalamic Hormones; D008543:Melanins; D010907:Pituitary Hormones; D017473:Receptors, Opioid, kappa; C019463:melanin-concentrating hormone