Estradiol Regulates Energy Balance by Ameliorating Hypothalamic Ceramide-Induced ER Stress
Ismael González-García,
Cristina Contreras,
Ánxela Estévez-Salguero,
Francisco Ruíz-Pino,
Benoit Colsh,
Iván Pensado,
Laura Liñares-Pose,
Eva Rial-Pensado,
Pablo B. Martínez de Morentin,
Johan Fernø,
Carlos Diéguez,
Rubén Nogueiras,
Hervé Le Stunff,
Christophe Magnan,
Manuel Tena-Sempere,
Miguel López
Affiliations
Ismael González-García
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Cristina Contreras
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Ánxela Estévez-Salguero
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Francisco Ruíz-Pino
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain; Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía, Córdoba, 14004, Spain
Benoit Colsh
CEA-Centre d’Etude de Saclay, Laboratoire d’étude du Métabolisme des Médicaments, Gif-sur-Yvette, France
Iván Pensado
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Laura Liñares-Pose
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Eva Rial-Pensado
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Pablo B. Martínez de Morentin
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Johan Fernø
Hormone Laboratory, Haukeland University Hospital, Bergen, 5021, Norway
Carlos Diéguez
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Rubén Nogueiras
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain
Hervé Le Stunff
Paris-Saclay Institute of Neuroscience, CNRS UMR 9197, Université Paris-Sud, University Paris Saclay, Orsay 91405 Cedex, France; Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, Paris, 75205, France
Christophe Magnan
Unité de Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Université Paris Diderot, Sorbonne Paris Cité, Paris, 75205, France
Manuel Tena-Sempere
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain; Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Córdoba, 14004, Spain; Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía, Córdoba, 14004, Spain; FiDiPro Program, Research Centre for Integrative Physiology and Pharmacology, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland
Miguel López
Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain; Corresponding author
Summary: Compelling evidence has shown that, besides its putative effect on the regulation of the gonadal axis, estradiol (E2) exerts a dichotomic effect on the hypothalamus to regulate food intake and energy expenditure. The anorectic effect of E2 is mainly mediated by its action on the arcuate nucleus (ARC), whereas its effects on brown adipose tissue (BAT) thermogenesis occur in the ventromedial nucleus (VMH). Here, we demonstrate that central E2 decreases hypothalamic ceramide levels and endoplasmic reticulum (ER) stress. Pharmacological or genetic blockade of ceramide synthesis and amelioration of ER stress selectively occurring in the VMH recapitulate the effect of E2, leading to increased BAT thermogenesis, weight loss, and metabolic improvement. These findings demonstrate that E2 regulation of ceramide-induced hypothalamic lipotoxicity and ER stress is an important determinant of energy balance, suggesting that dysregulation of this mechanism may underlie some changes in energy homeostasis seen in females. : González-García et al. demonstrate that estradiol (E2) acts in a precise area of the hypothalamus, named the ventromedial nucleus (VMH), to regulate brown fat thermogenesis. The actions of E2 are mediated by modulation of hypothalamic ceramides and ER stress. Keywords: estradiol, hypothalamus, ceramides, endoplasmic reticulum stress, brown adipose tissue, thermogenesis
