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Obesity negatively affects human health on a global scale. If we are to meet this challenge and design new medications, it is paramount that we gain a more complete understanding of the mechanisms regulating food intake and body weight. The 5-HTR agonist lorcaserin is a current obesity medication; however, neither the specific subset of 5-HTRs coordinating the therapeutic effect nor the neurochemical mediator targeted by these receptors has been fully defined. Earlier research genetically manipulating the receptor revealed that the subset of 5-HTRs co-expressed with brain POMC are both sufficient () and necessary () to modulate the anorectic effect of preclinical 5-HTR agonists. Given that 5-HTR agonists increase the activity of POMCneurons (), it was presumed that these neurons were the mediator of this effect. However, in light of recent findings that POMCneurons suppress appetite on a time scale of hours (), we considered whether 5-HTRs outside the ARC are necessary for 5-HTR's acute effects on feeding. Here we identify the function of a previously uncharacterized subset of 5-HTR expressing neurons, localized within the NTS, and reveal that the activation of this subpopulation has a significant and rapid impact on feeding behavior, and furthermore is sufficient to drive lorcaserin's acute reduction in food intake. In addition, we report that a subset of POMCneurons express 5-HTRs and that 5-HT and 5-HTR agonists directly activate POMCneurons via a post-synaptic, mixed cationic current. We also clarify that brain POMC is necessary for lorcaserin to influence feeding. Although POMC is not abundantly expressed within the NTS, we report that POMC in this region is required for 5-HTR agonist obesity medications to acutely reduce food intake. These data thereby reveal a subpopulation of 5-HTRs, which when pharmacologically activated significantly reduce food intake, identify that the mechanistic underpinnings of this acute effect is via POMC, and demonstrate that this discrete 5-HTsubpopulation is therapeutically relevant to obesity medications targeting the 5-HTRs.