The Role And Mechanisms Of Increased Plasma And Adipose MIF Following Olanzapine Treatment

Background Olanzapine is a first-line treatment of schizophrenia(SZ),but 60% of the patients develop different degrees of metabolic disorders.Unfortunately,the underlying mechanisms s are largely unknown.Macrophage migration inhibitory factor(MIF)is the first cytokine activity to be discovered.It can restrain macrophage movements and act as an upstream regulator of inflammatory and immune diseases.Recent studies have found that MIF plays an important role in the development of several metabolic diseases,such as obesity,type 2 diabetes and atherosclerosis.Our previous study found that MIF plays a key role in olanzapine-induced metabolic disorders.Our clinical studies show that the MIF non-5/5 genotype is associated with high plasma MIF levels and olanzapine-induced metabolic disorders in first-episode,drug-na?ve patients with schizophrenia.Our animal experiments show that the adipose high MIF levels,which caused by olanzapine treatment,lead to insulin resistance.Objective Based on these,this study will further explore(1)What's the role of MIF in metabolic disorders following olanzapine treatment in chronic SZ patients.(2)What's the molecular mechanisms underlying the expression and release of adipose MIF following olanzapine treatment.Methods(1)Clinical research: A total of 48 schizophrenic inpatients receiving monotherapy of chlorpromazine or olanzapine for more than 1year were recruited for this study in Shanghai Mental Health Center,Shanghai Jiao Tong University School of Medicine during the period from January 2012 to June 2012.In addition,48 age-and gender-matched healthy subjects were recruited as healthy controls.Firstly,compare the effects of high metabolic risk antipsychotics olanzapinea and chlorpromazine on plasma MIF levels and metabolic profiles.Secondly,investigate the relationship between plasma MIF levels and metabolic profiles in chronic SZ.(2)Animal and cell experiments: First,construct adipose MIF-increase mice models to explore the relationship between the expression of adipose MIF and PAR2.Secondly,construct PAR2-deficiency mice models to investigate whether PAR2/NF-?B signaling pathway regulates adipose MIF expression and release under non-olanzapine condition;Thirdly,treat wide type mice with olanzapine to establishof olanzapine-induced adipose MIF increase mice models,and further investigate whether olanzapine regulates adipose MIF expression via PAR2/NF-?B pathway.Results(1)? Compared with healthy controls,the plasma MIF levels significantly increased both in olanzapine and chlorpromazine group,but there was no statistical difference between the two antipsychotics groups.? Compared with chlorpromazine group,the levels of plasma leptin,plasma insulin and insulin resistance index(HOMA-IR)of olanzapine group significantly increased.? There were no statistical differences in body weight,fasting blood glucose,triglyceride,low density lipoprotein(LDL)and high-density lipoprotein(HDL)between the two antipsychotics groups.(2)? In MIF-increase mice models,the m RNA expression and protein level of adipose MIF significantly increased,which correlated with PAR2 m RNA expression.The m RNA expression of PREF1 also significantly increased,which correlated with PAR2 m RNA expression.? In PAR2-deficiency mice models,the expression and release of adipose MIF significantly decreased.PREF1 m RNA expression significantly decreased while FABP4 m RNA expression significantly increased.The phosphorylation of IKKa/b and NF-?B significantly decreased.? Following selective PAR2 agonist treatment,the m RNA expression of MIF and PREF1 significantly increased in preadipocytes.This is not the case in mature adipocytes.? In olanzapine-induced MIF increase mice models,the m RNA expression of PAR2 and PREF1 significantly decreased,while no change of FABP4.? The expression and release of MIF significantly increased in mature adipocytes following olanzapine treatment.Conclusion(1)The long-term treatment of olanzapine and chlorpromazine significantly increase plasma MIF levels in chronic SZ.The high plasma MIF levels may be a common feature of the long-term treatment of high metabolic risk antipsychotics.(2)The levels of plasma MIF correlate with plasma leptin and HOMA-IR in chronic SZ following olanzapine treatment.MIF is a potential clinical biomarker for olanzapine-induced metabolic side effects.(3)The mechanisms underlying the expression and release of adipose MIF are different with or wihout olanzapine treatment.In non-olanzapine condition,PAR2 increases adipose MIF levels by inhibiting adipogenesis and activating NF-?B pathway.Meanwhile,olanzapine increases MIF expression and release by directly stimulating maturea dipocytes.