Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis
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...
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doaj-cc60db24442144a08bb1ee9c99a521442020-11-25T01:49:09ZengElsevierCell Reports2211-12472015-07-0112336137010.1016/j.celrep.2015.06.041Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic GluconeogenesisMarc Schneeberger0Alicia G. Gómez-Valadés1Jordi Altirriba2David Sebastián3Sara Ramírez4Ainhoa Garcia5Yaiza Esteban6Anne Drougard7Albert Ferrés-Coy8Analía Bortolozzi9Pablo M. Garcia-Roves10John G. Jones11Bruno Manadas12Antonio Zorzano13Ramon Gomis14Marc Claret15Diabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainLaboratory of Metabolism, Department of Internal Medicine Specialties, Faculty of Medicine, University of Geneva, 1211 Geneva, SwitzerlandCIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainDepartment of Neurochemistry and Neuropharmacology, IIBB–CSIC–IDIBAPS, 08036 Barcelona, SpainDepartment of Neurochemistry and Neuropharmacology, IIBB–CSIC–IDIBAPS, 08036 Barcelona, SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainCNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3060-197 Cantanhede, PortugalCNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3060-197 Cantanhede, PortugalCIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainDiabetes and Obesity Research Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, SpainAlterations 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.http://www.sciencedirect.com/science/article/pii/S2211124715006531 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Marc Schneeberger Alicia G. Gómez-Valadés Jordi Altirriba David Sebastián Sara Ramírez Ainhoa Garcia Yaiza Esteban Anne Drougard Albert Ferrés-Coy Analía Bortolozzi Pablo M. Garcia-Roves John G. Jones Bruno Manadas Antonio Zorzano Ramon Gomis Marc Claret |
spellingShingle |
Marc Schneeberger Alicia G. Gómez-Valadés Jordi Altirriba David Sebastián Sara Ramírez Ainhoa Garcia Yaiza Esteban Anne Drougard Albert Ferrés-Coy Analía Bortolozzi Pablo M. Garcia-Roves John G. Jones Bruno Manadas Antonio Zorzano Ramon Gomis Marc Claret Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis Cell Reports |
author_facet |
Marc Schneeberger Alicia G. Gómez-Valadés Jordi Altirriba David Sebastián Sara Ramírez Ainhoa Garcia Yaiza Esteban Anne Drougard Albert Ferrés-Coy Analía Bortolozzi Pablo M. Garcia-Roves John G. Jones Bruno Manadas Antonio Zorzano Ramon Gomis Marc Claret |
author_sort |
Marc Schneeberger |
title |
Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis |
title_short |
Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis |
title_full |
Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis |
title_fullStr |
Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis |
title_full_unstemmed |
Reduced α-MSH Underlies Hypothalamic ER-Stress-Induced Hepatic Gluconeogenesis |
title_sort |
reduced α-msh underlies hypothalamic er-stress-induced hepatic gluconeogenesis |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2015-07-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2211124715006531 |
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