TY - JOUR AU - Cui, Donghong AU - Peng, Yanmin AU - Zhang, Chengfang AU - Li, Zezhi AU - Su, Yousong AU - Qi, Yadan AU - Xing, Mengjuan AU - Li, Jia AU - Kim, Grace E. AU - Su, Kevin N. AU - Xu, Jinjie AU - Wang, Meiti AU - Ding, Wenhua AU - Piecychna, Marta AU - Leng, Lin AU - Hirasawa, Michiru AU - Jiang, Kaida AU - Young, Lawrence AU - Xu, Yifeng AU - Qi, Dake AU - Bucala, Richard T1 - Macrophage migration inhibitory factor mediates metabolic dysfunction induced by atypical antipsychotic therapy PY - 2018/11/01/ AB - 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 antiā€“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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI93090 VL - 128 IS - 11 UR - https://doi.org/10.1172/JCI93090 SP - 4997 EP - 5007 PB - The American Society for Clinical Investigation ER -