The adipose-derived hormone, leptin, is a critical regulator of metabolism, that acts through the long form of its receptor, Lepr, within the brain to reduce energy intake, and to increase energy expenditure by adaptive thermogenesis. The cellular pathways mediating the anorectic actions of leptin have been identified, but those mediating the thermogenic effects have proven difficult to decipher. Here we identify a specific population of neuron in the dorsomedial hypothalamic nucleus (DMH), containing the RFamide neuropeptide, PrRP, which is sensitive to leptin signalling. A separate population of leptin-insensitive PrRP neurons in the brainstem is required, instead, for the satiating actions of the gut-derived hormone, cholecystokinin (CCK). Mice homozygous for a loxSTOPlox-PrRP allele are obese and do not respond to leptin or to CCK. Cre recombinase-mediated reactivation of PrRP only in brainstem neurons rescues the anorectic actions of CCK, but reactivation also in the hypothalamus is required to re-establish the thermogenic effect of leptin. PrRP neurons in the DMH respond to leptin injection, and knock out of Lepr selectively in these cells blocks leptin’s ability to induce adaptive thermogenesis, reducing energy expenditure and resulting in obesity. Thus, these data identify a distinct population of PrRP neuron in the hypothalamus that is required for the thermogenic actions of leptin, separate from the brainstem population mediating the satiating effects of CCK.