{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:43:41Z","timestamp":1792273421633,"version":"4.4.0"},"reference-count":100,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T00:00:00Z","timestamp":1624320000000},"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>Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozapine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine\u2019s adverse metabolic effects\u2014such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy\u2014was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver damage, fatty liver scores, glucose homeostasis, renal impairment, and retinopathy in mice fed a high fat diet (HFD). We discovered that obese mice treated with clozapine gained more weight and had greater kidney, liver, and retroperitoneal and epididymal fat pad masses; higher daily food efficiency; higher serum or hepatic triglyceride, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels; and higher hepatic lipid regulation marker expression than did the HFD-fed control mice. Furthermore, the clozapine group mice exhibited insulin resistance, poorer insulin sensitivity, greater glucose intolerance, and less Akt phosphorylation; their GLUT4 expression was lower, they had renal damage, more reactive oxygen species, and IL-1 expression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione peroxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-\u03baB expression; a net negative chromium balance occurred because more chromium was excreted through urine, and this influenced chromium mobilization, which did not help overcome the hyperglycemia. Our clozapine group had considerably higher fatty liver scores, which was supported by the findings of lowered adiponectin protein levels and increased FASN protein, PNPLA3 protein, FABP4 mRNA, and SREBP1 mRNA levels. We conclude that clozapine can worsen nonalcoholic fatty liver disease, diabetes, and kidney and retinal injury. Therefore, long-term administration of clozapine warrants higher attention.<\/jats:p>","DOI":"10.3390\/ijms22136680","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T13:02:10Z","timestamp":1624366930000},"page":"6680","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Clozapine Worsens Glucose Intolerance, Nonalcoholic Fatty Liver Disease, Kidney Damage, and Retinal Injury and Increases Renal Reactive Oxygen Species Production and Chromium Loss in Obese Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0577-3339","authenticated-orcid":false,"given":"Geng-Ruei","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Yueh","family":"Liu","sequence":"additional","affiliation":[{"name":"Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Cheng","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Veterinary Medicine, National Taiwan University, 4 Section, 1 Roosevelt Road, Taipei 100046, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8954-6151","authenticated-orcid":false,"given":"Chao-Min","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Fen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen-Wei","family":"Lin","sequence":"additional","affiliation":[{"name":"Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan"},{"name":"General Education Center, Chaoyang University of Technology, 168 Jifeng Eastern Road, Taichung 413310, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Chen","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Asia University Hospital, 222 Fuxin Road, Wufeng District, Taichung 413505, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng District, Taichung 413305, Taiwan"},{"name":"Division of Cardiovascular Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404332, Taiwan"},{"name":"College of Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Chun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huei-Jyuan","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Hsun","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Taichung Veterans General Hospital, 4 Section, 1650 Taiwan Boulevard, Taichung 407219, Taiwan"},{"name":"Faculty of Medicine, National Yang Ming Chiao Tung University, 2 Section, 155 Linong Street, Beitou District, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chee-Hong","family":"Chan","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 505029, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuen-Fu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 912301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1007\/s00213-020-05746-y","article-title":"A systematic review and meta-analysis of the association between clozapine and norclozapine serum levels and peripheral adverse drug reactions","volume":"238","author":"Tan","year":"2021","journal-title":"Psychopharmacology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1192\/S0007125000296918","article-title":"Clinical efficacy of clozapine in treatment-refractory schizophrenia: An 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