{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T03:38:13Z","timestamp":1789270693537,"version":"build-2803163510"},"reference-count":45,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"723","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,11,22]]},"abstract":"<jats:p>Despite their high degree of effectiveness in the management of psychiatric conditions, exposure to antipsychotic drugs, including olanzapine and risperidone, is frequently associated with substantial weight gain and the development of diabetes. Even before weight gain, a rapid rise in circulating leptin concentrations can be observed in most patients taking antipsychotic drugs. To date, the contribution of this hyperleptinemia to weight gain and metabolic deterioration has not been defined. Here, with an established mouse model that recapitulates antipsychotic drug\u2013induced obesity and insulin resistance, we not only confirm that hyperleptinemia occurs before weight gain but also demonstrate that hyperleptinemia contributes directly to the development of obesity and associated metabolic disorders. By suppressing the rise in leptin through the use of a monoclonal leptin-neutralizing antibody, we effectively prevented weight gain, restored glucose tolerance, and preserved adipose tissue and liver function in antipsychotic drug\u2013treated mice. Mechanistically, suppressing excess leptin resolved local tissue and systemic inflammation typically associated with antipsychotic drug treatment. We conclude that hyperleptinemia is a key contributor to antipsychotic drug\u2013associated weight gain and metabolic deterioration. Leptin suppression may be an effective approach to reducing the undesirable side effects of antipsychotic drugs.<\/jats:p>","DOI":"10.1126\/scitranslmed.ade8460","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T18:58:40Z","timestamp":1700679520000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":32,"title":["Hyperleptinemia contributes to antipsychotic drug\u2013associated obesity and metabolic disorders"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9209-8206","authenticated-orcid":true,"given":"Shangang","family":"Zhao","sequence":"first","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6712-7431","authenticated-orcid":true,"given":"Qian","family":"Lin","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2624-6474","authenticated-orcid":true,"given":"Wei","family":"Xiong","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8173-7367","authenticated-orcid":true,"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6738-0130","authenticated-orcid":true,"given":"Leon","family":"Straub","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6291-0750","authenticated-orcid":true,"given":"Dinghong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4745-8513","authenticated-orcid":true,"given":"Rizaldy","family":"Zapata","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9382-8517","authenticated-orcid":true,"given":"Qingzhang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2588-6648","authenticated-orcid":true,"given":"Xue-Nan","family":"Sun","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6787-3920","authenticated-orcid":true,"given":"Zhuzhen","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Life Sciences, Wuhan University, Wuhan, Hubei Sheng 430072, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2596-3167","authenticated-orcid":true,"given":"Jan-Bernd","family":"Funcke","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2060-4835","authenticated-orcid":true,"given":"Chao","family":"Li","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiuhwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1650-1363","authenticated-orcid":true,"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Children\u2019s Nutrition Research Center, Department of Pediatric, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1837-7618","authenticated-orcid":true,"given":"Nisi","family":"Jiang","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6070-5008","authenticated-orcid":true,"given":"Guannan","family":"Li","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3725-7726","authenticated-orcid":true,"given":"Ziying","family":"Xu","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1748-0525","authenticated-orcid":true,"given":"Steven C.","family":"Wyler","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May-Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1193-8155","authenticated-orcid":true,"given":"Juli","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Cell Systems &amp; Anatomy and Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8615-2413","authenticated-orcid":true,"given":"Xianlin","family":"Han","sequence":"additional","affiliation":[{"name":"Sam and Ann Barshop Institute for Longevity and Aging Studies, Division of Endocrinology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine M.","family":"Kusminski","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4348-2180","authenticated-orcid":true,"given":"Ningyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9309-2335","authenticated-orcid":true,"given":"Zhiqiang","family":"An","sequence":"additional","affiliation":[{"name":"Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel K.","family":"Elmquist","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Osborn","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."},{"name":"Peter O\u2019Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0680-3392","authenticated-orcid":true,"given":"Philipp E.","family":"Scherer","sequence":"additional","affiliation":[{"name":"Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1801490"},{"issue":"12","key":"e_1_3_2_3_2","first-page":"18","article-title":"Weight gain with atypical antipsychotics: Evidence and insights","volume":"68","author":"Henderson D. C.","year":"2007","unstructured":"D. C.\u00a0Henderson, Weight gain with atypical antipsychotics: Evidence and insights. J. Clin. Psychiatry 68Suppl 12, 18\u201326 (2007).","journal-title":"J. Clin. Psychiatry"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI93362"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20202484"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2021.815456"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.5483\/BMBRep.2022.55.6.026"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2015.03.004"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.2337\/db10-0449"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36930-y"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2010.05.060"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-021-01528-y"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07684-y"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-75624-2"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1350"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2017.02.003"},{"key":"e_1_3_2_17_2","first-page":"323","article-title":"Negative correlation between serum S100B and leptin levels in schizophrenic patients during treatment with clozapine and risperidone: Preliminary evidence","volume":"15","author":"Hendouei N.","year":"2016","unstructured":"N.\u00a0Hendouei, S. H.\u00a0Hosseini, A.\u00a0Panahi, Z.\u00a0Khazaeipour, F.\u00a0Barari, A.\u00a0Sahebnasagh, S.\u00a0Ala, Negative correlation between serum S100B and leptin levels in schizophrenic patients during treatment with clozapine and risperidone: Preliminary evidence. Iran. J.\u00a0Pharm. Res. 15, 323\u2013330 (2016).","journal-title":"Iran. J.\u00a0Pharm. Res."},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1177\/070674370204700805"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.07.005"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001147R"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.08.005"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.v61n1006"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.765905"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22010409"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(02)00102-2"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v11.i31.4822"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2022.02.020"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.9.1822"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.2174\/18715265112129990032"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2016.209"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2014.10.070"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2020.100995"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1097\/00004714-199902000-00011"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10911-008-9069-5"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyt.2022.874705"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.31887\/DCNS.2014.16.4\/jpouget"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.280.2.E334"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011376"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80062-3"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2014.1693"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.05.011"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.04.003"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00024"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.2337\/db17-0323"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI130239"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.005"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.ade8460","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T18:45:14Z","timestamp":1705430714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.ade8460"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,22]]},"references-count":45,"journal-issue":{"issue":"723","published-print":{"date-parts":[[2023,11,22]]}},"alternative-id":["10.1126\/scitranslmed.ade8460"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.ade8460","relation":{},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,22]]},"assertion":[{"value":"2022-09-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-10-17","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eade8460"}}