Abstract 362 Neonatal Disease Oriented Research: Molecular Events and Brain Injury Poster Symposium, Tuesday, 5/4

Leptin, a ≈ 16 kD translated & secreted product of the ob gene is synthesized by the adipocytes, circulates & crosses the blood-brain barrier to interact with leptin receptors in the adult hypothalamus. Leptin also regulates the hypothalamic synthesis/release of various neuropeptides, thus inhibiting appetite. We have previously demonstrated higher circulating leptin concentrations in the postnatal mouse & rat (BBRC 238:44-47, 1997, Ped Res 44:168-174, 1998) vs the adult, the biological significance of which remains unknown. To determine the biologic function of leptin in the postnatal period, we administered 1 µg of murine leptin (n=7 litters) or vehicle (n=10 litters) intracerebroventricularly (ICV) daily between 2-7d in Sprague-Dawley rats, & investigated the effect upon body weight gain, food intake, hypothalamic mechanisms, & the hormonal milieu at 8d, 22d, 90d & 120d. Data were analyzed by the Wilcoxan-Mann Whitney test using exact significance levels. Leptin caused a decline in body wt. on 8d (30%; p=0.002), which persisted until 90d (18%; p=0.009), & was noted only in the 120d females (20; p=0.002). Paralleling this observation, food intake (g/d) declined in the 90d (20%) & 120d (25%) females (p<0.05). ICV leptin caused an initial decline in the 8d paraventricular & arcuate nuclear leptin receptor immunoreactivity (60%; p=0.008), but upregulated these receptors in the 120d females (40%; p=0.008). These changes were associated with a 2 to 3-fold decline in paraventricular & arcuate nuclear neuropeptide Y (NPY) (orexigenic) immunoreactivity at 8d, 22d, & 120d females only (p=0.008) along with a 30-60% increase in α-melanocyte stimulating hormone (MSH) (anorexigenic) in the dorsomedial nuclei at 22d & 120d (p=0.008). ICV leptin administration also caused no change in plasma glucose, but led to hyperinsulinemia in the 8d & the 120d females (p=0.01). Concomitantly, hypercorticosteronism (p=0.008) with a 30-60% decline in plasma leptin levels occurred only in the 120d females (p=0.008). We conclude that postnatal ICV leptin administration: 1]caused a diminution in food intake and body weight which persisted only in the adult females, 2]suppressed hypothalamic leptin receptors initially but resulted in an increased receptor sensitivity in the adult 120d females, 3]concomitantly suppressed hypothalamic NPY amounts while enhancing α-MSH levels postnatally & in the adult females, and 4] resulted in hyperinsulinemia, hypercorticosteronism & hypoleptinemia peripherally. We speculate that leptin plays a vital role in accomplishing satiety in the newborn. The effects of neonatal ICV hyperleptinism persist & change the phenotype of the adult female. This altered phenotype is associated with a hormonal imbalance consistent with a catabolic state. [NIH-HD 25024, 33997]