[논문]The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain

Li, Li; Yoo, Eun-Seon; Li, Xiujuan; Wyler, Steven C.; Chen, Xiameng; Wan, Rong; Arnold, Amanda G.; Birnbaum, Shari G.; Jia, Lin; Sohn, Jong-Woo; Liu, Chen

doi:10.1084/jem.20202484

[해외논문] The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain 원문보기

The Journal of experimental medicine, v.218 no.7, 2021년, pp.e20202484 -

Li, Li (The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX) , Yoo, Eun-Seon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea) , Li, Xiujuan (The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX) , Wyler, Steven C. (The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX) , Chen, Xiameng (The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX) , Wan, Rong (The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX) , Arnold, Amanda G. (The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX) , Birnbaum, Shari G. (Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX) , Jia, Lin (Depart) , Sohn, Jong-Woo , Liu, Chen

Abstract ▼ AI-Helper

Li et al. develop a new mouse model that recapitulates risperidone-induced metabolic syndrome. Using a combination of transcriptomic, genetic, and electrophysiological approaches, they show that risperidone targets hypothalamic MC4Rs to cause weight gain and that setmelanotide, an MC4R agonist, mitigates its metabolic side effects.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.

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