Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine—another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.
The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain
Disclosures: The authors declare no competing interests exist.
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Li Li, Eun-Seon Yoo, Xiujuan Li, Steven C. Wyler, Xiameng Chen, Rong Wan, Amanda G. Arnold, Shari G. Birnbaum, Lin Jia, Jong-Woo Sohn, Chen Liu; The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain. J Exp Med 5 July 2021; 218 (7): e20202484. doi: https://doi.org/10.1084/jem.20202484
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