title: Reduction of Hypothalamic Endoplasmic Reticulum Stress Activates Browning of White Fat and Ameliorates Obesity.
abstract: The chaperone GRP78/BiP (glucose-regulated protein 78 kDa/binding immunoglobulin protein) modulates protein folding in reply to cellular insults that lead to endoplasmic reticulum (ER) stress. This study investigated the role of hypothalamic GRP78 on energy balance, with particular interest in thermogenesis and browning of white adipose tissue (WAT). For this purpose, we used diet-induced obese rats and rats administered thapsigargin, and by combining metabolic, histologic, physiologic, pharmacologic, thermographic, and molecular techniques, we studied the effect of genetic manipulation of hypothalamic GRP78. Our data showed that rats fed a high-fat diet or that were centrally administered thapsigargin displayed hypothalamic ER stress, whereas genetic overexpression of GRP78 specifically in the ventromedial nucleus of the hypothalamus was sufficient to alleviate ER stress and to revert the obese and metabolic phenotype. Those effects were independent of feeding and leptin but were related to increased thermogenic activation of brown adipose tissue and induction of browning in WAT and could be reversed by antagonism of β3 adrenergic receptors. This evidence indicates that modulation of hypothalamic GRP78 activity may be a potential strategy against obesity and associated comorbidities.
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|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 Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Ismael
authors.initials: I
authors.lastname: González-García
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Seoane-Collazo
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez-Sánchez
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Liñares-Pose
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Rial-Pensado
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|Department of Clinical Science, K.G. Jebsen Center for Diabetes Research, University of Bergen, Bergen, Norway.
authors.forename: Johan
authors.initials: J
authors.lastname: Fernø
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.|Department of Cell Biology, Physiology and Immunology, University of Córdoba, and Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía, Córdoba, Spain.|Finland Distinguished Professor Program, Department of Physiology, University of Turku, Turku, Finland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.|Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Casals
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Nogueiras
authors.affiliation: Department of Physiology, Centro Singular de Investigación en Medicina Molecular e Enfermidades Crónicas, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain m.lopez@usc.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013655:Taurochenodeoxycholic Acid / Q000627:therapeutic use; D013696:Temperature; D022722:Thermogenesis / Q000187:drug effects
chemical_list: D005230:Fatty Acids, Nonesterified; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine