title: Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance.
abstract: Hypothalamic endoplasmic reticulum (ER) stress is a key mechanism leading to obesity. Here, we demonstrate that ceramides induce lipotoxicity and hypothalamic ER stress, leading to sympathetic inhibition, reduced brown adipose tissue (BAT) thermogenesis, and weight gain. Genetic overexpression of the chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) in the ventromedial nucleus of the hypothalamus (VMH) abolishes ceramide action by reducing hypothalamic ER stress and increasing BAT thermogenesis, which leads to weight loss and improved glucose homeostasis. The pathophysiological relevance of this mechanism is demonstrated in obese Zucker rats, which show increased hypothalamic ceramide levels and ER stress. Overexpression of GRP78 in the VMH of these animals reduced body weight by increasing BAT thermogenesis as well as decreasing leptin and insulin resistance and hepatic steatosis. Overall, these data identify a triangulated signaling network involving central ceramides, hypothalamic lipotoxicity/ER stress, and BAT thermogenesis as a pathophysiological mechanism of obesity.
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Contreras
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: González-García
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez-Sánchez
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Seoane-Collazo
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain; Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallés, 08195 Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Jacas
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain; Department of Biochemistry and Molecular Biology, School of Pharmacy, Institut de Biomedicina (IBUB), Universitat de Barcelona, 08028 Barcelona, Spain.
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
authors.affiliation: Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.affiliation: Department of Surgery, CIMUS, University of Santiago de Compostela-Instituto de Invesstiagacion Sanitaria, 15782 Santiago de Compostela, Spain; Service of Ophthalmology, Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gonzalez
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain; Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallés, 08195 Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Casals
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.affiliation: Department of Pharmacology, University of Iowa, Iowa City, IA 52242, USA; Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain. Electronic address: m.lopez@usc.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D007031:Hypothalamus / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D022722:Thermogenesis / Q000502:physiology*; D015431:Weight Loss
chemical_list: D002518:Ceramides