Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy
Donghong Cui, … , Dake Qi, Richard Bucala
Donghong Cui, … , Dake Qi, Richard Bucala
Published October 8, 2018
Citation Information: J Clin Invest. 2018;128(11):4997-5007. https://doi.org/10.1172/JCI93090.
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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 5

MIF downregulates lipolysis and upregulates adipogenesis following olanzapine treatment.

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MIF downregulates lipolysis and upregulates adipogenesis following olanz...
WT mice were treated with olanzapine (Olz, 3 mg/kg) or vehicle control for 2 months, and adipose tissue was isolated for the measurement of hormone-sensitive lipase (HSL) activation (A) by Western blotting. MIF (50 ng/ml and 400 ng/ml for 1 to 24 hours of treatment) was added to cultured 3T3-L1 adipocytes and (B) phospho- and total-HSL evaluated by Western blot, and (C) HSL mRNA by qPCR (400 ng/ml MIF). The GAPDH Western blot shown in B is from a parallel gel run contemporaneously on identical samples. (D) Adipose transcript levels of lipoprotein lipase (LPL), PPARγ, CD36, and fatty acid synthase (FAS) were quantified by qPCR in WT or Mif–/– mice treated for 2 months with olanzapine or vehicle. (E) H&E staining of representative adipose tissue sections (n = 5 examined per experimental group) was performed to evaluate adipocyte hypertrophy in WT and Mif–/– mice following 2 months of treatment with olanzapine (Olz) or vehicle (V). Original magnification, ×40. A 2-tailed Student’s t test or 1-way ANOVA plus Tukey’s test was used for statistical analysis. Mean ± SD; *P < 0.05 shows an increase versus vehicle or control; #P < 0.05 shows a reduction versus vehicle or control; n = 4–5 for each animal group.