AbstractCalcitonin receptor (Calcr)-expressing neurons of the nucleus tractus solitarius (NTS; Calcr^NTS cells) contribute to the long-term control of food intake and body weight. Here, we show that Prlh-expressing NTS (Prlh^NTS) neurons represent a subset of Calcr^NTS cells and that Prlh expression in these cells restrains body weight gain in the face of high fat diet challenge in mice. To understand the relationship of Prlh^NTS cells to hypothalamic feeding circuits, we determined the ability of Prlh^NTS-mediated signals to overcome enforced activation of AgRP neurons. We found that Prlh^NTS neuron activation and Prlh overexpression in Prlh^NTS cells abrogates AgRP neuron-driven hyperphagia and ameliorates the obesity of mice deficient in melanocortin signaling or leptin. Thus, enhancing Prlh-mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity, demonstrating that NTS-mediated signals can override the effects of orexigenic hypothalamic signals on long-term energy balance.