Chang G.-RLiu H.-YWEI-CHENG YANGWang C.-MWu C.-FLin J.-WLin W.-LWang Y.-CLin T.-CLiao H.-JHou P.-HChan C.-HLin C.-F.2022-04-252022-04-25202116616596https://www.scopus.com/inward/record.uri?eid=2-s2.0-85108222939&doi=10.3390%2fijms22136680&partnerID=40&md5=ed6edfa1ace7b98355634d66ee3bc294https://scholars.lib.ntu.edu.tw/handle/123456789/605990Clozapine is widely employed in the treatment of schizophrenia. Compared with that of atypical first-generation antipsychotics, atypical second-generation antipsychotics such as clozap-ine have less severe side effects and may positively affect obesity and blood glucose level. However, no systematic study of clozapine’s adverse metabolic effects—such as changes in kidney and liver function, body weight, glucose and triglyceride levels, and retinopathy—was conducted. This research investigated how clozapine affects weight, the bodily distribution of chromium, liver dam-age, 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 effi-ciency; 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 re-sistance, 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 ex-pression, and, finally, their levels of antioxidative enzymes (superoxide dismutase, glutathione pe-roxidase, and catalase) were lower. Moreover, clozapine reduced the thickness of retinal cell layers and increased iNOS and NF-κB 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. ? 2021 by the author. Licensee MDPI, Basel, Switzerland.ChromiumClozapineFatty liver diseaseGlucose intoleranceObesityReactive oxygen speciesRenal damageRetinal injuryadiponectinalanine aminotransferaseantioxidantaspartate aminotransferasebiological markercatalasechromiumclozapinecreatininefatty acid binding protein 4fatty acid synthaseglucoseglucose transporter 4glutathione peroxidaseimmunoglobulin enhancer binding proteininducible nitric oxide synthaseinsulininterleukin 1messenger RNAprotein kinase Bprotein PNPLA3reactive oxygen metabolitesterol regulatory element binding protein 1superoxide dismutasetriacylglycerolunclassified drugFABP4 protein, humanfatty acid binding proteinNOS2 protein, humanSREBF1 protein, humanalanine aminotransferase blood levelanimal experimentanimal modelanimal tissueArticleaspartate aminotransferase blood levelbody weight gaincontrolled studycreatinine blood leveldiabetes mellitusdisease exacerbationepididymis fatfood intakeglucose homeostasisglucose intolerancehyperglycemiainsulin blood levelinsulin resistanceinsulin sensitivitykidney diseasekidney injurylipid dietlipid liver levelliver functionliver injurymalemorphometrymousemRNA expression levelnonalcoholic fatty livernonhumanobesityprotein expression levelprotein phosphorylationreal time polymerase chain reactionregulatory mechanismretina cellretina injuryretinal thicknessretinopathyretroperitoneal fat padsignal transductionthicknesstriacylglycerol blood levelurea nitrogen blood levelurinary excretionadipocyteanimalcomplicationdisease modelfluorescent antibody techniquegene expressiongene expression regulationgeneticsimmunohistochemistrylivermetabolismmouse mutantretina diseaseAdipocytesAnimalsBiomarkersBody Weights and MeasuresDisease Models, AnimalFatty Acid-Binding ProteinsFluorescent Antibody TechniqueGene ExpressionGene Expression RegulationGlucose IntoleranceImmunohistochemistryInsulinKidney DiseasesLiverMiceMice, ObeseNitric Oxide Synthase Type IINon-alcoholic Fatty Liver DiseaseProto-Oncogene Proteins c-aktReactive Oxygen SpeciesRetinal DiseasesSterol Regulatory Element Binding Protein 1[SDGs]SDG3journal article10.3390/ijms22136680342064602-s2.0-85108222939