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 November 1, 2018; First published October 8, 2018
Citation Information: J Clin Invest. 2018;128(11):4997-5007. https://doi.org/10.1172/JCI93090.
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Categories: 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 6

MIF regulates abnormal lipid storage in liver and skeletal muscle, which may contribute to the occurrence of whole-body insulin resistance.

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MIF regulates abnormal lipid storage in liver and skeletal muscle, which...
(A) Plasma free fatty acid (FFA) and (B) triglyceride (TG) levels were measured in blood samples collected from vehicle- or olanzapine-treated WT mice. (C) Fat distribution in heart, liver, and skeletal muscle was quantified in mice by MRI scanning using the T2*-IDEAL water-fat decomposition method (1). Plasma FFA (D) and TG (E) levels were quantified in olanzapine-treated WT and Mif–/– mice. Panel F shows the comparison of fat distribution in liver and skeletal muscle between WT and Mif–/– mice following 2 months of olanzapine treatment. In a separate experiment, intraperitoneal glucose tolerance (G) and insulin tolerance (H) tests (GTT, ITT) were performed following 2 months of olanzapine treatment in WT or Mif–/– mice. Glucose and insulin tolerance tests (I, J) in mice that received IgG or anti–MIF monoclonal antibody (2 μg/day) i.c.v. by an osmotic pump, accompanied with olanzapine for 2 months as in Figure 3, I and J. Mean ± SE shown in G–I; mean ± SD in the other panels. *P < 0.05 versus vehicle in A–C; #P < 0.05 versus WT Olz in D–F; *P < 0.05 versus other groups in G and H; #P < 0.05 versus IgG group in I and J. Data in A–F were analyzed by Student’s t test and G–J were analyzed by multivariate ANOVA. For each animal group, n = 4–5. Olz: olanzapine; Anti-MIF: anti–MIF antibody. (K) Schematic diagram for a proposed mechanism of olanzapine-induced metabolic dysfunction. Olanzapine induces MIF expression in the hypothalamus, which upregulates AMPK phosphorylation and food intake. In peripheral tissues, olanzapine stimulates MIF expression and release from adipose tissue, which may contribute to circulating levels of MIF. In adipose tissue, MIF also mediates glucose metabolism, adipogenesis, and adipolysis, leading to adiposity. Hyperlipidemia contributes to increased TG storage in liver and skeletal muscle, leading to insulin resistance in peripheral tissues.