Nutritional Effect In Hypothalamic Endothelial Tight Junction During Postnatal Development

Childhood obesity has drastically increased over recent decades, and it has been linked with advanced puberty. In animal models, increased body fat, and leptin, secreted by adipocytes, during early life, advances pubertal age. Leptin levels peak around postnatal day 10 (P10) in mice and has a crucial role in brain development. Pericytes and endothelial cells of brain micro-vessels express the leptin receptor (LepR) short form, involved in leptin transport across the blood brain barrier in adults. We previously found that genes associated with vasculogenesis were differentially expressed in the mediobasal hypothalamus during pubertal transition and in leptin deficient adult mice ( Lep ob vs C57BL6). Diet-induced obesity and leptin administration in rodents alter the permeability of the blood brain barrier. Here, we explored if leptin-induced changes in endothelial barrier formation and function occur in prepubertal mice. Using a qPCR array, we found changes in the expression of several genes linked to endothelial tight junction formation during postnatal development. C57BL6 female mice at P10 showed higher Claudin 5 ( Cldn5 ) Crb3, and Pard6b expression in the hypothalamus as compared to P20 and P60. Using litter size manipulation as an early-life overnutrition paradigm, we found that female mice from small litters—which were consistently overweight compared to controls from normal-sized litters— showed no changes in the expression of these genes at both P10 and P20. In primary culture of brain microvascular endothelial cells from P10 mice, leptin treatment (50ng/ml) increased the permeability to 1KDa and 3KDa tracers. We are currently exploring if these developmental changes are influenced by the presence of leptin during postnatal development using young Lep ob mice. Our current findings suggest that fluctuating leptin levels during early postnatal development alter hypothalamic tight junction integrity and micro-vessel permeability, as observed in adults, independent of changes in gene expression. Whether these effects contribute to early-onset obesity and advanced puberty is still unknown. R01HD106962 to CFE, R21HD109485 to CFE and CSM, Michigan Diabetes Research Institute Diabetes Interdisciplinary Studies Program grant to AAZ and CFE. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.