Infant satiety depends on transient expression of cholecystokinin‐1 receptors on ependymal cells lining the third ventricle in mice

Key pointsIn mammals, satiety‐controlling mechanisms develop before the switch from ingestive behaviour from milk suckling to regular food intake; however, the underlying mechanisms are currently unknown. We show that absence of the cholecystokinin‐1 (CCK‐1) receptor gene significantly increases suckling pup weight, regardless of maternal genotype in mice. CCK‐1 receptor expression was observed in satiety‐controlling regions such as the hypothalamus, caudal brainstem, nodose ganglion and pylorus, which is consistent with suggested receptor function in adults, whereas corresponding receptor expression was low to non‐existent at pre‐weanling stages. Third ventricle ependymal tanycyte‐like cells transiently expressed CCK‐1 receptors at critical developmental stages, and gastrointestinal milk filling upregulated cFos expression in these cells. Localized blocking of ependymal CCK‐1 receptors was sufficient to produce overweight pups, suggesting that the ependymal CCK‐1 receptor is an infant‐specific satiety controller.Abstract  Cholecystokinin (CCK) is a hypothetical controller for suckling and infancy body weight, although the underlying mechanisms remain unclear. Therefore, the present study analysed the mechanisms using mice lacking the CCK‐1 receptor (CCK1R–/–). Although CCK1R–/– mice displayed normal weights at birth and adulthood, CCK1R–/– pups had enlarged adipocytes and were overweight from the first to second week after birth, regardless of maternal genotype. The lacZ reporter gene assay and/or calcium imaging analysis demonstrated that CCK‐1 receptors were abundant in satiety‐controlling regions such as the hypothalamus, brainstem, nodose ganglion and pylorus in adults, whereas these signals were few to lacking at pre‐weanling stages. At postnatal day (PD) 6, the increase in cFos expression in the medullary nucleus tractus solitarius was similarly triggered by gastrointestinal milk‐ or saline filling in both genotypes, further indicating immature CCK‐1 receptor function in an ascending satiety‐controlling system during infancy. Conversely, third ventricle ependymal tanycyte‐like cells expressed CCK‐1 receptors with expression peaking at PD6. At PD6, wild‐type but not CCK1R–/– mice had increased cFos immunoreactivity in ependymal cells following gastrointestinal milk filling whereas the response became negligible at PD12. In addition, ependymal cFos was not increased by saline filling, indicating that these responses are dependent on CCK‐1 receptors, developmental stage and nutrients. Furthermore, body weights of wild‐type pups were transiently increased by blocking ependymal CCK receptor function with microinjection of a CCK‐1 antagonist, but not a CCK‐2 antagonist. Hence, we demonstrate de novo functions of ependymal CCK‐1 receptors and reveal a new aspect of infant satiety‐controlling mechanisms.