title: Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK.
abstract: Estrogens play a major role in the modulation of energy balance through central and peripheral actions. Here, we demonstrate that central action of estradiol (E2) inhibits AMP-activated protein kinase (AMPK) through estrogen receptor alpha (ERα) selectively in the ventromedial nucleus of the hypothalamus (VMH), leading to activation of thermogenesis in brown adipose tissue (BAT) through the sympathetic nervous system (SNS) in a feeding-independent manner. Genetic activation of AMPK in the VMH prevented E2-induced increase in BAT-mediated thermogenesis and weight loss. Notably, fluctuations in E2 levels during estrous cycle also modulate this integrated physiological network. Together, these findings demonstrate that E2 regulation of the VMH AMPK-SNS-BAT axis is an important determinant of energy balance and suggest that dysregulation in this axis may account for the common changes in energy homeostasis and obesity linked to dysfunction of the female gonadal axis.
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
authors.forename: Pablo B
authors.initials: PB
authors.lastname: Martínez de Morentin
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
authors.forename: Ismael
authors.initials: I
authors.lastname: González-García
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
authors.forename: Luís
authors.initials: L
authors.lastname: Martins
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Lage
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
authors.forename: Diana
authors.initials: D
authors.lastname: Fernández-Mallo
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
authors.forename: Noelia
authors.initials: N
authors.lastname: Martínez-Sánchez
authors.affiliation: 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 Universitario Reina Sofia (HURS), Córdoba, 14004, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruíz-Pino
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands; Department of Hypothalamic Integration Mechanisms, Netherlands Institute of Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Science, Amsterdam, 1105 BA, The Netherlands; Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui, 230026, P. R. China.
authors.forename: Ji
authors.initials: J
authors.lastname: Liu
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), 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 Universitario Reina Sofia (HURS), Córdoba, 14004, Spain.
authors.forename: Leonor
authors.initials: L
authors.lastname: Pinilla
authors.affiliation: Department of Morphological Sciences, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, 15782, Spain.
authors.forename: Rosalía
authors.initials: R
authors.lastname: Gallego
authors.affiliation: Diabetes Research Unit, EBRC-827, Boston Medical Center, Boston, MA 02118, USA.
authors.forename: Asish K
authors.initials: AK
authors.lastname: Saha
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands; Department of Hypothalamic Integration Mechanisms, Netherlands Institute of Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Science, Amsterdam, 1105 BA, The Netherlands.
authors.forename: Andries
authors.initials: A
authors.lastname: Kalsbeek
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.affiliation: Department of Endocrinology and Metabolism, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Bisschop
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
authors.forename: Carlos
authors.initials: C
authors.lastname: Diéguez
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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.
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: 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 Universitario Reina Sofia (HURS), Córdoba, 14004, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Tena-Sempere
authors.affiliation: Department of Physiology, Research Center of Molecular Medicine and Chronic Diseases (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. Electronic address: m.lopez@usc.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: López
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D004734:Energy Metabolism / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D007031:Hypothalamus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010053:Ovary / Q000293:injuries; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013564:Sympathetic Nervous System / Q000378:metabolism; D022722:Thermogenesis / Q000187:drug effects*
chemical_list: D047628:Estrogen Receptor alpha; D004958:Estradiol; D055372:AMP-Activated Protein Kinases