title: Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis.
abstract: Alterations in ER homeostasis have been implicated in the pathophysiology of obesity and type-2 diabetes (T2D). Acute ER stress induction in the hypothalamus produces glucose metabolism perturbations. However, the neurobiological basis linking hypothalamic ER stress with abnormal glucose metabolism remains unknown. Here, we report that genetic and induced models of hypothalamic ER stress are associated with alterations in systemic glucose homeostasis due to increased gluconeogenesis (GNG) independent of body weight changes. Defective alpha melanocyte-stimulating hormone (α-MSH) production underlies this metabolic phenotype, as pharmacological strategies aimed at rescuing hypothalamic α-MSH content reversed this phenotype at metabolic and molecular level. Collectively, our results posit defective α-MSH processing as a fundamental mediator of enhanced GNG in the context of hypothalamic ER stress and establish α-MSH deficiency in proopiomelanocortin (POMC) neurons as a potential contributor to the pathophysiology of T2D.
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Endocrinology and Nutrition, Hospital Clínic, School of Medicine, University of Barcelona, 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Schneeberger
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Alicia G
authors.initials: AG
authors.lastname: Gómez-Valadés
authors.affiliation: Laboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Jordi
authors.initials: J
authors.lastname: Altirriba
authors.affiliation: CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sebastián
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Ramírez
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Garcia
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Yaiza
authors.initials: Y
authors.lastname: Esteban
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain.
authors.forename: Anne
authors.initials: A
authors.lastname: Drougard
authors.affiliation: Department of Neurochemistry and Neuropharmacology, IIBB-CSIC-IDIBAPS, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Ferrés-Coy
authors.affiliation: Department of Neurochemistry and Neuropharmacology, IIBB-CSIC-IDIBAPS, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 28029 Madrid, Spain.
authors.forename: Analía
authors.initials: A
authors.lastname: Bortolozzi
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Garcia-Roves
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3060-197 Cantanhede, Portugal.
authors.forename: John G
authors.initials: JG
authors.lastname: Jones
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3060-197 Cantanhede, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Manadas
authors.affiliation: CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain; Institute for Research in Biomedicine (IRB Barcelona), 08028 Barcelona, Spain; Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Department of Endocrinology and Nutrition, Hospital Clínic, School of Medicine, University of Barcelona, 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Gomis
authors.affiliation: Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain. Electronic address: mclaret@clinic.ub.es.
authors.forename: Marc
authors.initials: M
authors.lastname: Claret
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D005943:Gluconeogenesis; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism*
chemical_list: D000521:alpha-MSH