The Thermogenic Effect of Leptin Is Dependent on a Distinct Population of Prolactin-Releasing Peptide Neurons in the Dorsomedial Hypothalamus

Leptin is a critical regulator of metabolism, which acts on brain receptors (Lepr) to reduce energy intake and increase energy expenditure. Some of the cellular pathways mediating leptin’s anorectic actions are identified, but those mediating the thermogenic effects have proven more difficult to decipher. We define a population of neurons in the dorsomedial hypothalamic nucleus (DMH) containing the RFamide PrRP, which is activated by leptin. Disruption of Lepr selectively in these cells blocks thermogenic responses to leptin and causes obesity. 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). Global deletion of PrRP (in a loxSTOPlox-PrRP mouse) results in obesity and attenuated responses to leptin and CCK. Cre-recombinase-mediated reactivation of PrRP in brainstem rescues the anorectic actions of CCK, but reactivation in the hypothalamus is required to re-establish the thermogenic effect of leptin. [Display omitted] •PrRP neurons in the hypothalamic dorsomedial nucleus are sensitive to leptin•Cell-specific Lepr KO blocks leptin-induced thermogenesis and causes obesity•Global deletion of PrRP attenuates responses to leptin and CCK•Distinct PrRP populations are needed for thermogenesis and satiety effects Leptin acts on the brain to regulate food intake and energy expenditure. Dodd et al. identify a population of PrRP neurons in the dorsomedial hypothalamus that directly respond to leptin to increase core body temperature. PrRP neurons in the brainstem are required, instead, for the satiating actions of gut-derived cholecystokinin.