Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy
Donghong Cui, Yanmin Peng, Chengfang Zhang, Zezhi Li, Yousong Su, Yadan Qi, Mengjuan Xing, Jia Li, Grace E. Kim, Kevin N. Su, Jinjie Xu, Meiti Wang, Wenhua Ding, Marta Piecychna, Lin Leng, Michiru Hirasawa, Kaida Jiang, Lawrence Young, Yifeng Xu, Dake Qi, Richard Bucala
Donghong Cui, Yanmin Peng, Chengfang Zhang, Zezhi Li, Yousong Su, Yadan Qi, Mengjuan Xing, Jia Li, Grace E. Kim, Kevin N. Su, Jinjie Xu, Meiti Wang, Wenhua Ding, Marta Piecychna, Lin Leng, Michiru Hirasawa, Kaida Jiang, Lawrence Young, Yifeng Xu, Dake Qi, Richard Bucala
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Research Article Metabolism

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

Abstract

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.

Authors

Donghong Cui, Yanmin Peng, Chengfang Zhang, Zezhi Li, Yousong Su, Yadan Qi, Mengjuan Xing, Jia Li, Grace E. Kim, Kevin N. Su, Jinjie Xu, Meiti Wang, Wenhua Ding, Marta Piecychna, Lin Leng, Michiru Hirasawa, Kaida Jiang, Lawrence Young, Yifeng Xu, Dake Qi, Richard Bucala

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Figure 4

Olanzapine increases plasma MIF levels and MIF expression in adipose tissue.

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Olanzapine increases plasma MIF levels and MIF expression in adipose tis...
WT and MIF knockout (Mif–/–) C57BL/6 mice were administered vehicle or 3 mg/kg olanzapine per day for 2 months. Plasma MIF concentrations in WT mice with or without olanzapine treatment were measured by ELISA (A). Adipose, liver, and skeletal muscle tissues were subsequently isolated and (B) tissue MIF content was evaluated by Western blot. Olanzapine stimulation for 24 hours induced a dose-dependent increase in intracellular MIF protein levels in fully differentiated 3T3-L1 adipocytes (C) and induced MIF release into conditioned medium (D) (DMSO was employed as vehicle). Values are mean ± SD. A 2-tailed Student’s t test was used for data analysis in A, B, and D and 1-way ANOVA followed by Tukey’s test was used in C. Mean ± SD; *P < 0.05 versus vehicle or control in A, B, and C, and versus DMSO in D. For each animal group, n = 4–5 in A and B; n = 5 in C, and n = 3 in D.