A role for the brainstem in regulating body weight

The control of food intake requires neural and hormonal signals between the gut and the central nervous system, forming a 'gut-brain' axis. Cholecystokinin (CCK) is a gut hormone that signals via vagal afferents to the brain to terminate a meal. Previous studies from our lab have demonstrated that central signalling by the neuropeptide, prolactin-releasing peptide (PrRP), is required for CCK-induced satiety. PrRP is expressed in two brain areas involved in body-weight regulation: the hypothalamus and brainstem. Using the Cre-LoxP system in transgenic mice, we dissected separate populations of hypothalamic and brainstem PrRP neurons to assess their roles in mediating the effects of CCK. LSL-PrRP mice, with a loxSTOPlox codon between the PrRP promoter and coding sequence, do not express PrRP, are obese and do not respond to CCK. However, Cre-mediated rescue of brainstem PrRP expression prevents obesity and restores the anorectic feeding response to CCK. Together, these results demonstrate that PrRP expression in the brainstem, not the hypothalamus, is sufficient to mediate the effects of CCK and affect overall body weight. Thus, the CCK-PrRP pathway is a major component of the gut-brain axis and is a potential target in the development of novel treatments for obesity.