{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T13:21:50Z","timestamp":1787664110633,"version":"build-2736575974"},"reference-count":30,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22H00396"],"award-info":[{"award-number":["22H00396"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23KK0126"],"award-info":[{"award-number":["23KK0126"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2026,9]]},"abstract":"ABSTRACT<\/jats:title>\n \n Aim<\/jats:title>\n Brown adipose tissue thermogenesis is widely considered an important effector mechanism in fever and emotionally induced hyperthermia (psychogenic fever), and increases in interscapular temperature are commonly interpreted as evidence of brown adipose tissue activation. Yet direct evidence for this interpretation remains limited and conflicting. Here, we tested these assumptions using complementary genetic and surgical approaches in rats.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We generated uncoupling protein 1 knockout rats, in which canonical brown adipose tissue thermogenesis is abolished, and examined body temperature responses to systemic inflammation induced by lipopolysaccharide and to emotional stressors, including restraint and cage exchange. In separate experiments, interscapular brown adipose tissue was surgically removed in wild\u2010type rats.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Despite profound impairment of cold\u2010 and \u03b2\n \u2083<\/jats:sub>\n \u2010adrenergic\u2010induced thermogenesis, uncoupling protein 1 deletion did not affect lipopolysaccharide\u2010 or stress\u2010induced increases in core or interscapular temperature. Likewise, removal of interscapular brown adipose tissue did not alter the interscapular temperature response. Thus, increases in interscapular temperature occurred in the absence of both uncoupling protein 1 and interscapular brown adipose tissue. Consistent with these findings, immune challenge and emotional stress induced little or no change in thermogenic gene expression and had minimal effects on tissue mass, in contrast to robust activation by \u03b2\n \u2083<\/jats:sub>\n \u2010adrenergic stimulation.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Fever and psychogenic hyperthermia in rats do not require uncoupling protein 1\u2010mediated brown adipose tissue thermogenesis. Furthermore, increases in interscapular temperature are not necessarily indicative of brown adipose tissue thermogenesis, challenging a widely held interpretation of these phenomena.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/apha.70300","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:29:41Z","timestamp":1787660981000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune\u2010Induced Fever and Psychogenic Hyperthermia Can Occur Independently of Uncoupling Protein 1\u2010Mediated Brown Adipose Tissue Thermogenesis"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4842-6110","authenticated-orcid":false,"given":"Takashi","family":"Matsuwaki","sequence":"first","affiliation":[{"name":"Laboratory of Veterinary Physiology Graduate School of Agricultural and Life Sciences, The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8177-1744","authenticated-orcid":false,"given":"Wakana","family":"Harigai","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Physiology Graduate School of Agricultural and Life Sciences, The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4029-8257","authenticated-orcid":false,"given":"Vladimir","family":"Maksimov","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences Link\u00f6ping University Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaro","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Graduate School of Agricultural and Life Sciences, The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4823-0318","authenticated-orcid":false,"given":"Kazuyuki","family":"Uchida","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Graduate School of Agricultural and Life Sciences, The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5273-7221","authenticated-orcid":false,"given":"James K.","family":"Chambers","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology Graduate School of Agricultural and Life Sciences, The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1491-5127","authenticated-orcid":false,"given":"Keitaro","family":"Yamanouchi","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Physiology Graduate School of Agricultural and Life Sciences, The University of Tokyo Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6131-0403","authenticated-orcid":false,"given":"Anna","family":"Eskilsson","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences Link\u00f6ping University Link\u00f6ping Sweden"},{"name":"Clinical Rheumatology, Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences Link\u00f6ping University Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6928-4473","authenticated-orcid":false,"given":"Anders","family":"Blomqvist","sequence":"additional","affiliation":[{"name":"Division of Neurobiology, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences Link\u00f6ping University Link\u00f6ping Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"issue":"1","key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1152\/physrev.00015.2003","article-title":"Brown Adipose Tissue: Function and Physiological Significance","volume":"84","author":"Cannon B.","year":"2004","journal-title":"Physiological Reviews"},{"issue":"3","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1089\/dna.2022.0662","article-title":"Prostaglandin E(2) Production by Brain Endothelial Cells and the Generation of Fever","volume":"42","author":"Blomqvist A.","year":"2023","journal-title":"DNA and Cell Biology"},{"issue":"5","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"R1207","DOI":"10.1152\/ajpregu.00109.2011","article-title":"Central Circuitries for Body Temperature Regulation and Fever","volume":"301","author":"Nakamura K.","year":"2011","journal-title":"American Journal of Physiology. Regulatory, Integrative and Comparative Physiology"},{"issue":"12","key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1111\/j.1460-9568.2005.04515.x","article-title":"Direct Pyrogenic Input From Prostaglandin EP3 Receptor\u2010Expressing Preoptic Neurons to the Dorsomedial Hypothalamus","volume":"22","author":"Nakamura Y.","year":"2005","journal-title":"European Journal of Neuroscience"},{"issue":"1","key":"e_1_2_9_6_1","first-page":"85","article-title":"Brown Adipose Tissue as a Source of Heat During Pyrogen\u2010Induced Fever","volume":"43","author":"Szekely M.","year":"1973","journal-title":"Acta Physiologica Academiae Scientiarum Hungaricae"},{"issue":"3","key":"e_1_2_9_7_1","first-page":"265","article-title":"Endotoxin Fever in the Rat","volume":"53","author":"Szekely M.","year":"1979","journal-title":"Acta Physiologica Academiae Scientiarum Hungaricae"},{"issue":"2","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.cmet.2014.05.018","article-title":"Psychological Stress Activates a Dorsomedial Hypothalamus\u2010Medullary Raphe Circuit Driving Brown Adipose Tissue Thermogenesis and Hyperthermia","volume":"20","author":"Kataoka N.","year":"2014","journal-title":"Cell Metabolism"},{"issue":"4","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"E1135","DOI":"10.1152\/ajpendo.00425.2006","article-title":"Brown Fat UCP1 Is Not Involved in the Febrile and Thermogenic Responses to IL\u20101\u03b2 in Mice","volume":"292","author":"Okamatsu\u2010Ogura Y.","year":"2007","journal-title":"American Journal of Physiology. Endocrinology and Metabolism"},{"issue":"6","key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1111\/ejn.12463","article-title":"Intact Brown Adipose Tissue Thermogenesis Is Required for Restorative Sleep Responses After Sleep Loss","volume":"39","author":"Szentirmai \u00c9.","year":"2014","journal-title":"European Journal of Neuroscience"},{"issue":"24","key":"e_1_2_9_11_1","doi-asserted-by":"crossref","first-page":"7455","DOI":"10.1113\/JP272971","article-title":"The Complementary and Divergent Roles of Uncoupling Proteins 1 and 3 in Thermoregulation","volume":"594","author":"Riley C. L.","year":"2016","journal-title":"Journal of Physiology"},{"issue":"4","key":"e_1_2_9_12_1","doi-asserted-by":"crossref","first-page":"5863","DOI":"10.1096\/fj.201902945R","article-title":"The Generation of Immune\u2010Induced Fever and Emotional Stress\u2010Induced Hyperthermia in Mice Does Not Involve Brown Adipose Tissue Thermogenesis","volume":"34","author":"Eskilsson A.","year":"2020","journal-title":"FASEB Journal"},{"key":"e_1_2_9_13_1","doi-asserted-by":"crossref","DOI":"10.1017\/CBO9780511565595","volume-title":"Temperature Regulation in Laboratory Rodents","author":"Gordon C. J.","year":"1993"},{"issue":"1","key":"e_1_2_9_14_1","doi-asserted-by":"crossref","DOI":"10.1038\/s42003-026-09534-w","article-title":"Neither Rats nor Mice Have a Broad Thermoneutral Zone: Implications for Physiological Studies","volume":"9","author":"Jacobsen J. M.","year":"2026","journal-title":"Communications Biology"},{"key":"e_1_2_9_15_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.autneu.2021.102918","article-title":"Central Sympathetic Network for Thermoregulatory Responses to Psychological Stress","volume":"237","author":"Nakamura K.","year":"2022","journal-title":"Autonomic Neuroscience"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/978-981-97-4584-5_10","article-title":"Central Mechanisms of Thermoregulation and Fever in Mammals","volume":"1461","author":"Nakamura K.","year":"2024","journal-title":"Advances in Experimental Medicine and Biology"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/978-1-0716-2990-1_14","volume-title":"Transgenesis: Methods and Protocols","author":"Sato M.","year":"2023"},{"key":"e_1_2_9_18_1","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1146\/annurev.med.48.1.307","article-title":"Brown Adipose Tissue, Beta 3\u2010Adrenergic Receptors, and Obesity","volume":"48","author":"Lowell B. B.","year":"1997","journal-title":"Annual Review of Medicine"},{"issue":"1","key":"e_1_2_9_19_1","first-page":"R332","article-title":"Methodology of Fever Research: Why Are Polyphasic Fevers Often Thought to Be Biphasic?","volume":"275","author":"Romanovsky A. A.","year":"1998","journal-title":"American Journal of Physiology"},{"issue":"1","key":"e_1_2_9_20_1","doi-asserted-by":"crossref","DOI":"10.1186\/s12929-017-0370-8","article-title":"Comprehensive Comparison of Three Different Animal Models for Systemic Inflammation","volume":"24","author":"Seemann S.","year":"2017","journal-title":"Journal of Biomedical Science"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","DOI":"10.3389\/fendo.2020.00498","article-title":"UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes","volume":"11","author":"Ikeda K.","year":"2020","journal-title":"Frontiers in Endocrinology"},{"issue":"6628","key":"e_1_2_9_22_1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1038\/387090a0","article-title":"Mice Lacking Mitochondrial Uncoupling Protein Are Cold\u2010Sensitive but Not Obese","volume":"387","author":"Enerback S.","year":"1997","journal-title":"Nature"},{"key":"e_1_2_9_23_1","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1146\/annurev-physiol-020518-114546","article-title":"Central Mechanisms for Thermoregulation","volume":"81","author":"Morrison S. F.","year":"2019","journal-title":"Annual Review of Physiology"},{"issue":"4","key":"e_1_2_9_24_1","doi-asserted-by":"crossref","first-page":"R1239","DOI":"10.1152\/ajpregu.90723.2008","article-title":"Nonshivering Thermogenesis Without Interscapular Brown Adipose Tissue Involvement During Conditioned Fear in the Rat","volume":"296","author":"Marks A.","year":"2009","journal-title":"American Journal of Physiology. Regulatory, Integrative and Comparative Physiology"},{"issue":"8","key":"e_1_2_9_25_1","doi-asserted-by":"crossref","DOI":"10.1242\/jeb.218479","article-title":"Skeletal Muscle Thermogenesis Induction by Exposure to Predator Odor","volume":"223","author":"Gorrell E.","year":"2020","journal-title":"Journal of Experimental Biology"},{"issue":"6","key":"e_1_2_9_26_1","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.bbabio.2010.02.033","article-title":"Cold Tolerance of UCP1\u2010Ablated Mice: A Skeletal Muscle Mitochondria Switch Toward Lipid Oxidation With Marked UCP3 Up\u2010Regulation Not Associated With Increased Basal, Fatty Acid\u2010 or ROS\u2010Induced Uncoupling or Enhanced GDP Effects","volume":"1797","author":"Shabalina I. G.","year":"2010","journal-title":"Biochimica et Biophysica Acta"},{"key":"e_1_2_9_27_1","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2019.00470","article-title":"Important Trends in UCP3 Investigation","volume":"10","author":"Pohl E. E.","year":"2019","journal-title":"Frontiers in Physiology"},{"issue":"3","key":"e_1_2_9_28_1","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.metabol.2014.11.007","article-title":"Low Levels of Lipopolysaccharide Modulate Mitochondrial Oxygen Consumption in Skeletal Muscle","volume":"64","author":"Frisard M. I.","year":"2015","journal-title":"Metabolism"},{"issue":"24","key":"e_1_2_9_29_1","doi-asserted-by":"crossref","first-page":"7151","DOI":"10.1113\/JP273485","article-title":"Drugs and Bugs: Turning on the Heat Through UCP1 and UCP3","volume":"594","author":"Harper M. E.","year":"2016","journal-title":"Journal of Physiology"},{"issue":"22","key":"e_1_2_9_30_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms232213805","article-title":"LPS\u2010Induced Inhibition of miR\u2010143 Expression in Brown Adipocytes Promotes Thermogenesis and Fever","volume":"23","author":"Liu J.","year":"2022","journal-title":"International Journal of Molecular Sciences"},{"issue":"9","key":"e_1_2_9_31_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jlr.2024.100617","article-title":"Brown Adipose Tissue Facilitates the Fever Response Following Infection With \n Salmonella enterica Serovar Typhimurium in Mice","volume":"65","author":"Li M.","year":"2024","journal-title":"Journal of Lipid Research"}],"container-title":["Acta Physiologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apha.70300","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/apha.70300","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apha.70300","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:50:41Z","timestamp":1787662241000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apha.70300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":30,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1111\/apha.70300"],"URL":"https:\/\/doi.org\/10.1111\/apha.70300","archive":["Portico"],"relation":{},"ISSN":["1748-1708","1748-1716"],"issn-type":[{"value":"1748-1708","type":"print"},{"value":"1748-1716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]},"assertion":[{"value":"2026-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70300"}}