PROJECT SUMMARY Antipsychotic drug (APD)-induced metabolic syndrome is a pressing clinical problem affecting millions of patients. However, the difficulty in modeling their metabolic effects in laboratory animals has significantly hindered relevant mechanistic studies. To this end, we have developed new mouse models that recapitulate human metabolic syndrome caused by two commonly prescribed APDs (olanzapine and risperidone). Metabolic analyses revealed that drug-induced hyperphagia is the driving force behind weight gain in both models. Using bulk RNA sequencing, we investigated how APDs altered gene expression in the hypothalamus—a brain region that is critical for appetite control. Our analyses revealed that the melanocortin 4 receptor (Mc4r) was among those that were directly regulated by APD treatment. Furthermore, we found that the obesogenic effect of olanzapine and risperidone depends on Mc4r in Sim1 neurons. Moreover, we found that APDs reduced hypothalamic Mc4r mRNAs before the weight gain. Remarkably, whole-cell electrophysiology experiments demonstrated for the first time that olanzapine and risperidone acutely inhibited Mc4r-expressing neurons in the paraventricular nucleus of the hypothalamus. Furthermore, this inhibition was mediated by a postsynaptic potassium conductance. Collectively, these findings provided the first experimental evidence linking deficits in hypothalamic MC4R signaling to APD-induced metabolic syndrome. In the current project, we propose a multi-discipline approach to investigate the mechanisms underlying 1) how olanzapine and risperidone interact with MC4Rs and perturb their functions; 2) how they inhibit the activity of Mc4r neurons; 3) how both drugs alter the transcriptional and chromatin landscapes in hypothalamic neurons at the single-cell level. These studies have important clinical implications based on the suggestions that MC4R can be a novel therapeutic target for APD-induced weight gain, and that they may guide the development of next-generation antipsychotic medications with fewer metabolic side effects.