d-Fenfluramine (d-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy ofd-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT2CRs) significantly attenuatedd-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT2CRs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects ofd-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property ofd-Fen. Thus, our results identify a neurochemically defined neural circuit through whichd-Fen influences appetite and thereby indicate that this 5-HT2CR/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss.