The Peripheral and Central Cross Talk Mediated by Adipose MIF-A Novel Mechanism of Hyperphagia following Olanzapine Treatment

Olanzapine is one of the first-line antipsychotic medications but it usually induces metabolic side effects, characterized by obesity. We previously indicated that olanzapine leads to hyperphagia through the effects of a proinflammatory cytokine, macrophage migration inhibitory factor (MIF) in the hypothalamus. However, whether olanzapine's upregulated peripheral MIF could affect the central mechanism is currently unknown. Our present study found that olanzapine increases ectopic expression of dopamine receptor 1 (DRD1) in adipocytes which relatively upregulates MIF expression and release through a PKA/CREB signaling pathway. In global MIF knockout mice, MIF accumulation appears in the hypothalamus following peripheral injection of recombinant MIF proteins, suggesting that peripheral MIF indeed travels to the hypothalamus. Mif Lung Tg mice (MIF overexpression in the lung) with increased circulating MIF levels had hyperphagia and activation of the CaMKKβ/AMPK/AgRP signaling pathway in the hypothalamus. Overall, our study for the first time proved that adipose-derived MIF is a crucial factor in regulating metabolic side effects induced by olanzapine. Disclosure X.Chen: None. Y.Huang: None. Y.Qi: None. L.Chen: None. L.Li: None. P.Gao: None. D.Cui: None. D.Qi: None. Funding National Sciences and Engineering Research Council of Canada (RGPIN-2017-04542); Canadian Institutes of Health Research (PJT-156116); China Scholarship Council (202106230212)