Circadian rhythm drives the responsiveness of leptin-mediated hypothalamic pathway of cholecystokinin-8

Cholecystokinin (CCK) and leptin act coordinately in the brain to regulate food intake and energy balance. Recently we have reported that CCK enhances the permeability of brain barriers to leptin and we have proposed that CCK enhances energy expenditure in rats by activating in the hypothalamus the janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway, which is coupled to leptin receptors. Because plasma leptin concentration follows a circadian rhythm (plasma leptin concentration rise maximal values during the night, after rats start eating), we have hypothesized that the interaction between leptin and CCK should be more intense in animals receiving CCK during the night, i.e., during periods of positive energy balance. In order to further characterize the physiological relevance of the interplay between leptin and CCK we have compared the effect of diurnal vs. nocturnal administration of the C-terminal octapeptide of CCK (CCK-8) on (i) body weight and food intake, and (ii) STAT3 activation, by analyzing phosphorylated STAT3 (pSTAT3) immunostaining within the arcuate nucleus of the hypothalamus. Our results show that CCK decreases body weight and food intake only after p.m. administration. Accordingly pSTAT3 immunostaining within the hypothalamus was more intense in p.m. than in a.m.-treated animals. These data suggest that the effect of CCK on leptin pathways follows a circadian rhythm linked to the energy balance status and gives further support to the interaction between leptin and CCK.