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

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. Antipsychotics are essential medications for millions of patients combating a wide variety of neuropsychiatric conditions such as schizophrenia, bipolar disorder, and autism spectrum disorders (Meltzer, 2013). Despite their broad efficacy, many antipsychotic drugs, especially atypical antipsychotics (AAPs), have been associated with drug-induced metabolic syndrome, which is characterized by excessive weight gain, dyslipidemia, and insulin resistance (Gohlke et al., 2012). Although morbid obesity