The Model Of Metabolic Syndrome Induced By Clozapine And Its Association With Inflammatory Pathways

Schizophrenia is a prevalent mental illness that has a high disability rate and an unclear pathogenesis.The introduction of antipsychotic drugs(APDs)has revolutionized the treatment of psychosis by quickly controlling psychotic symptoms and reducing the recurrence rate of psychotic episodes,thus improving the quality of life for patients with schizophrenia.However,the prolonged use of APDs is associated with significant metabolic disruptions,including weight gain,dysglycemia,and worsening cardiometabolic disease inherent to schizophrenia,which can progress to metabolic syndrome.The use of second-generation APDs like clozapine is particularly associated with a prominent metabolic syndrome(MS),which is a leading cause of the high mortality rate observed in schizophrenia.Inflammation appears to play a crucial role in both the intrinsic metabolic disturbances and drug-induced metabolic effects,although the underlying mechanisms are not well understood.This study examined the feasibility of using clozapine as a model to induce metabolic syndrome,and explored the evidence for the effect of antipsychotic drug-mediated metabolic disorders on systemic inflammation.The study also discussed the activation of inflammatory pathways and increased levels of inflammatory factors in both central and peripheral organs.Finally,the study delved into whether central inflammation and peripheral inflammation are related,influence each other,or have consistency.These results provide a deeper understanding of the mechanisms by which antipsychotic drugs cause metabolic disorders,improve our understanding of the relationship between metabolic adverse effects and the "therapeutic effect" of these drugs,and may lead to the development of new strategies to improve cognitive and metabolic outcomes.ObjectThe objective of this study is to create an animal model for clozapine-induced metabolic syndrome,observe the resulting glucose and lipid metabolic disruptions,examine the alterations in blood inflammatory factors,peripheral and central inflammatory factors,and inflammatory pathways,and discuss the possible mechanisms involved in inflammation.Method1.Effects of long-term administration of clozapine on glucose and lipid metabolism Adult C57BL/6 mice were randomly divided into three groups: control group,low-dose clozapine group and high-dose clozapine group,with 8 mice in each group.After one week of adaptive feeding,mice were fed with peanut butter pills containing clozapine for 10 weeks,and mice in the control group were given the same dose of empty peanut butter pills.The changes in body weight,food intake and water intake of the mice were recorded during the administration period.The serum glucose(Glu),total cholesterol(CHO)and triglyceride(TG)in each group were detected by chemiluminescence method.TG),high-density lipoprotein(HDL)and low-density lipoprotein(LDL)concentrations,and serum glycolipid,high-density lipoprotein and low-density lipoprotein levels were measured to evaluate the success of the model.Oral glucose tolerance test(OGTT)was used to evaluate the glucose tolerance of the control group and the model group.The concentrations of TNF-α,IL1β,IL6 and insulin(INS)in serum and tissues were detected by enzyme linked immunosorbent assay(ELISA).Hematoxylin-eosin(HE)staining was used to observe the morphological changes of liver and adipose tissue in the control group and the model group,and oil red staining was used to observe the lipid deposition in liver tissue cells.2.Effects of long-term clozapine administration on inflammatory factors and pathways in central and peripheral organsTranscriptome sequencing was used to analyze the differential expression of RNA in the prefrontal lobe of the normal group and the model group,and GO analysis and KEGG enrichment analysis were performed on the sequencing results.Western Blotting(WB)was used to detect the expression of STAT3/ERK/Gsk-3β signaling pathway related proteins in the prefrontal cortex(PFC)and liver tissue.ResultCompared with the control group,the body weight,serum insulin,CHO,TG and LDL levels of mice in the model group were significantly increased,and the fasting blood glucose concentration(FBG)of mice in the model group was significantly higher than that of the control group.The results of oral glucose tolerance test showed that the glucose tolerance of mice in the model group was poor.Glucose tolerance decreased and peripheral insulin resistance increased.HE staining showed steatosis of liver tissue in the model group,increased white adipose tissue,and significantly increased adipose cell volume in adipose tissue,suggesting serious disorder of glucose and lipid metabolism in the model group.Transcriptomic sequencing results showed that the top 10 pathways concentrated in GO and KEGG analysis contained inflammatory pathways and insulin resistance pathways,suggesting that the metabolic syndrome caused by clozapine may involve the activation of central inflammatory pathways and insulin resistance pathways,and the activation of central insulin pathways and insulin resistance pathways may participate in the process of peripheral metabolic disorders.WB results further demonstrated that long-term administration of clozapine can lead to increased levels of inflammatory factors in peripheral liver and central prefrontal lobe as well as increased levels of STAT3 phosphorylation,and the activation of inflammatory pathways is involved in the mechanism of metabolic syndrome induced by clozapine.ConclusionLong-term administration of clozapine induced metabolic syndrome in mice,characterized by impaired glucose and lipid metabolism,impaired liver function and lipid accumulation,as well as elevated serum inflammatory cytokines.In mice,clozapine can cause prefrontal insulin resistance and increased insulin levels which leading to chronic activation of the hepatic JAK-STAT3 pathway,thereby promoting the release of downstream inflammatory factors and promoting the development of metabolic syndrome.STAT3 may be the brain-liver axis linking factor of AAPs on central therapeutic effect and peripheral metabolic disorder.