{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:29:41Z","timestamp":1786681781972,"version":"build-2736575974"},"reference-count":42,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005230","name":"Natural Science Foundation of Chongqing","doi-asserted-by":"publisher","award":["cstc2020jcyj-msxmX0424"],"award-info":[{"award-number":["cstc2020jcyj-msxmX0424"]}],"id":[{"id":"10.13039\/501100005230","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Performance Incentive and Guidance Special Project of Scientific Research Organization, Chongqing Science and Technology","award":["cstc2021jxjl130024"],"award-info":[{"award-number":["cstc2021jxjl130024"]}]},{"award":["cstc2021jxjl130024"],"award-info":[{"award-number":["cstc2021jxjl130024"]}],"id":[{"id":"https:\/\/ror.org\/02sr2ee22","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Natural Science Foundation for Young Scholars of Sichuan Province","award":["2024NSFSC1565"],"award-info":[{"award-number":["2024NSFSC1565"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: This study investigates the role of ELOVL6 in the weight gain induced by olanzapine and the mechanisms underlying the female-specific response. Methods: An olanzapine-induced weight gain model in SD rats was developed. Transcriptome sequencing and metabolomics identified genes and metabolites linked to female-specific weight gain. Validation was conducted in HL7702 cells, and DNA pulldown, ChIP-qPCR, and molecular docking explored the molecular mechanism. A genetic polymorphism association study was also performed. Results: Female rats showed more pronounced weight gain compared to males following olanzapine treatment. Transcriptomic and metabolomics analyses revealed that olanzapine significantly upregulates hepatic ELOVL6 expression and long-chain fatty acid synthesis in females. Inhibition of ELOVL6 restores the elevated levels of the lipid, SREBP-1c and FAS induced by olanzapine. The transcription factor HNF-3\u03b1 is implicated in ELOVL6 regulation, and some olanzapine metabolites can directly interact with HNF-3\u03b1. Furthermore, a single-nucleotide polymorphism (SNP) at the ELOVL6 promoter -1427 bp correlates with weight gain in female patients. Conclusions: Olanzapine metabolites interact with HNF-3\u03b1, enhancing ELOVL6 transcription. The upregulated ELOVL6 promotes long-chain fatty acid synthesis via the SREBP-1c\/FAS pathway, contributing to female-specific weight gain.<\/jats:p>","DOI":"10.3390\/ph19081223","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T13:42:36Z","timestamp":1785850956000},"page":"1223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ELOVL6: A Key Factor in the Gender Differences of Olanzapine-Induced Weight Gain"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0910-9285","authenticated-orcid":false,"given":"Keke","family":"Che","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Southwest University, Beibei District, Chongqing 400715, China"},{"name":"Department of Pharmacy, Chongqing Academy of Medical Sciences, Chongqing General Hospital, Chongqing University, No. 118, Xingguang Avenue, Liangjiang New Area, Chongqing 401147, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9750-535X","authenticated-orcid":false,"given":"Dejuan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Chengdu Medical College, No. 783, Xindu Avenue, Xindu District, Chengdu 610500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Mental Health, North Sichuan Medical College, Maoyuan South Road, Shunqing District, Nanchong 637100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6037-5918","authenticated-orcid":false,"given":"Yanyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Chongqing Medical University, No. 1, Yixueyuan Road, Yuzhong District, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Liu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Southwest University, Beibei District, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8889-711X","authenticated-orcid":false,"given":"Changhua","family":"Hu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Southwest University, Beibei District, Chongqing 400715, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1001\/jamapsychiatry.2021.0015","article-title":"Association Between Cardiovascular Risk Factors and Cognitive Impairment in People With Schizophrenia: A Systematic Review and Meta-analysis","volume":"78","author":"Hagi","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"38\u201352; quiz 35\u201337, 53","DOI":"10.1017\/S1092852914000601","article-title":"Thinking and acting beyond the positive: The role of the cognitive and negative symptoms in schizophrenia","volume":"19","author":"Carbon","year":"2014","journal-title":"CNS Spectr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S0140-6736(21)01730-X","article-title":"Schizophrenia","volume":"399","author":"Jauhar","year":"2022","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S2215-0366(18)30511-X","article-title":"Prevalence of mental disorders in China: A cross-sectional epidemiological study","volume":"6","author":"Huang","year":"2019","journal-title":"Lancet Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/S0140-6736(18)31612-X","article-title":"The Lancet Commission on global mental health and sustainable development","volume":"392","author":"Patel","year":"2018","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1192\/S0007125000293653","article-title":"Olanzapine: A basic science update","volume":"174","author":"Bymaster","year":"1999","journal-title":"Br. 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