| First Author | Li L | Year | 2021 |
| Journal | J Exp Med | Volume | 218 |
| Issue | 7 | PubMed ID | 33978701 |
| Mgi Jnum | J:322187 | Mgi Id | MGI:6724861 |
| Doi | 10.1084/jem.20202484 | Citation | Li L, et al. (2021) The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain. J Exp Med 218(7) |
| abstractText | 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. |
