{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:04:45Z","timestamp":1774875885686,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,14]],"date-time":"2022-03-14T00:00:00Z","timestamp":1647216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the kappa-opioid receptor (k-OR) system is involved in mediating body weight changes associated with E2 withdrawal. Here, we document that body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1\u2212\/\u2212global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating weight gain and adiposity in OVX mice. These findings will help to define new therapies to manage metabolic disorders associated with low\/null E2 levels based on the modulation of central k-OR signaling.<\/jats:p>","DOI":"10.3390\/ijms23063118","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T03:06:10Z","timestamp":1647313570000},"page":"3118","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Kappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5104-6998","authenticated-orcid":false,"given":"Amparo","family":"Romero-Pic\u00f3","sequence":"first","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Instituto de Investigaci\u00f3n Sanitaria (IDIS), 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0285-7182","authenticated-orcid":false,"given":"Marta G.","family":"Novelle","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Instituto de Investigaci\u00f3n Sanitaria (IDIS), 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0645-6159","authenticated-orcid":false,"given":"Omar","family":"Al-Massadi","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Instituto de Investigaci\u00f3n Sanitaria (IDIS), 15782 Santiago de Compostela, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS\/SERGAS), Traves\u00eda da Choupana s\/n, 15706 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Beiroa","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda 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Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Instituto de Investigaci\u00f3n Sanitaria (IDIS), 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco","family":"Ruiz-Pino","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Instituto Maim\u00f3nides de Investigaci\u00f3n Biom\u00e9dica de C\u00f3rdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Cordoba, Hospital Universitario Reina Sof\u00eda, 14004 Cordoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Senra","sequence":"additional","affiliation":[{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Instituto de Investigaci\u00f3n Sanitaria (IDIS), 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7823-1648","authenticated-orcid":false,"given":"Miguel","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Instituto de Investigaci\u00f3n Sanitaria (IDIS), 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clemence","family":"Blouet","sequence":"additional","affiliation":[{"name":"MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, WT-MRC Institute of Metabolic Science, University of Cambridge, Cambridge CB2 OQQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Tena-Sempere","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Instituto Maim\u00f3nides de Investigaci\u00f3n Biom\u00e9dica de C\u00f3rdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology, University of Cordoba, Hospital Universitario Reina Sof\u00eda, 14004 Cordoba, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-9930","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Nogueiras","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Instituto de Investigaci\u00f3n Sanitaria (IDIS), 15782 Santiago de Compostela, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Di\u00e9guez","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBERobn), Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Center for Research in Molecular Medicine and Chronic Diseases, The Center for Research in 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