2. Academic Validation
  3. The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain

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

  • J Exp Med. 2021 Jul 5;218(7):e20202484. doi: 10.1084/jem.20202484.
Li Li  # 1,  Eun-Seon Yoo  # 2,  Xiujuan Li  # 1,  Steven C Wyler 1,  Xiameng Chen 1,  Rong Wan 1,  Amanda G Arnold 1,  Shari G Birnbaum 3 4,  Lin Jia 5,  Jong-Woo Sohn 2,  Chen Liu 1 6
Affiliations

Affiliations

  • 1 The Hypothalamic Research Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX.
  • 2 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
  • 3 Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX.
  • 4 Peter O'Donnell Jr. Brain Institute, The University of Texas Southwestern Medical Center, Dallas, TX.
  • 5 Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX.
  • 6 Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX.
  • # Contributed equally.
PMID: 33978701 DOI: 10.1084/jem.20202484
Abstract

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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