Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy

Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with th...

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Bibliographic Details
Published in:The Journal of clinical investigation 2018-11, Vol.128 (11), p.4997-5007
Main Authors: Cui, Donghong, Peng, Yanmin, Zhang, Chengfang, Li, Zezhi, Su, Yousong, Qi, Yadan, Xing, Mengjuan, Li, Jia, Kim, Grace E, Su, Kevin N, Xu, Jinjie, Wang, Meiti, Ding, Wenhua, Piecychna, Marta, Leng, Lin, Hirasawa, Michiru, Jiang, Kaida, Young, Lawrence, Xu, Yifeng, Qi, Dake, Bucala, Richard
Format: Article
Language:English
Subjects:
Adipocytes
Adipose tissue
Agouti-related protein
Antipsychotics
Appetite
Biomedical research
Complications
Diabetes
Food intake
Gene deletion
Gene expression
Genotype & phenotype
Genotypes
Glucose
Hypothalamus
Insulin
Insulin resistance
Kinases
Leukocyte migration
Lipolysis
Liver
Macrophage migration inhibitory factor
Metabolism
Obesity
Olanzapine
Pharmacogenomics
Plasma
Protein kinase
Proteins
Psychotropic drugs
Skeletal muscle
Weight control
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Summary:Atypical antipsychotics are highly effective antischizophrenic medications but their clinical utility is limited by adverse metabolic sequelae. We investigated whether upregulation of macrophage migration inhibitory factor (MIF) underlies the insulin resistance that develops during treatment with the most commonly prescribed atypical antipsychotic, olanzapine. Olanzapine monotherapy increased BMI and circulating insulin, triglyceride, and MIF concentrations in drug-naive schizophrenic patients with normal MIF expression, but not in genotypic low MIF expressers. Olanzapine administration to mice increased their food intake and hypothalamic MIF expression, which led to activation of the appetite-related AMP-activated protein kinase and Agouti-related protein pathway. Olanzapine also upregulated MIF expression in adipose tissue, which reduced lipolysis and increased lipogenic pathways. Increased plasma lipid concentrations were associated with abnormal fat deposition in liver and skeletal muscle, which are important determinants of insulin resistance. Global MIF-gene deletion protected mice from olanzapine-induced insulin resistance, as did intracerebroventricular injection of neutralizing anti-MIF antibody, supporting the role of increased hypothalamic MIF expression in metabolic dysfunction. These findings uphold the potential pharmacogenomic value of MIF genotype determination and suggest that MIF may be a tractable target for reducing the metabolic side effects of atypical antipsychotic therapy.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI93090