Postnatal intracerebroventricular exposure to leptin causes an altered adult female phenotype

Abstract

We investigated the effect of daily intracerebroventricular (ICV) leptin administration (neonatal age 2-7 days) on hypothalamic neuropeptides (neuropeptide Y, ␣-melanocyte-stimulating hormone) that regulate food intake, body weight (BW) gain, and the metabolic/hormonal profile in suckling (8 and 21 days) and adult rat (35, 60, 90, and 120 days). ICV leptin (0.16 g ⅐ g BW Ϫ1 ⅐ dose Ϫ1 ; n ϭ 70) led to a postnatal decline in BW (P ϭ 0.0002) that persisted only in the adult females (P ϭ 0.002). The postnatal decline in BW due to leptin was associated with a decline in food intake (P ϭ 0.01) and hypothalamic leptin receptor (P ϭ 0.008) and neuropeptide Y (P ϭ 0.008) immunoreactivities and an increase in ␣-melanocyte-stimulating hormone (P ϭ 0.008) immunoreactivity. In addition, hyperinsulinemia (P ϭ 0.01) with hypocorticosteronemia (P ϭ 0.007) occurred during the postnatal period with hypercorticosteronemia (P ϭ 0.007) and hypoleptinemia (P ϭ 0.008) and an increase in leutinizing hormone (P ϭ 0.01) in the adult male and female progeny. Persistent hyperinsulinemia (P ϭ 0.015) with hyperglycemia (P ϭ 0.008) and glucose intolerance (P ϭ 0.001) were observed only in the adult female. We conclude that postnatal leptin administration alters the adult female phenotype and speculate that this may relate to retention of leptin sensitivity resulting in a lipoatrophic state. development; ob gene; food intake; hyperinsulinemia; neuropeptide Y LEPTIN, THE TRANSLATED AND SECRETED PRODUCT of the ob gene (65), is primarily synthesized by adipose tissue (25), interacts with membrane-associated leptin receptors in various tissues (13,24,54), and regulates energy homeostasis by matching rates of energy expenditure with energy intake (25,42,45,46,61).The biological actions of leptin are composed of direct peripheral (on target organs) and central (via hypothalamic and sympathetic nervous system) effects. Peripherally, leptin affects the metabolism of various tissues including the pancreatic ␤-islets (30, 66), adipocytes (38, 42), skeletal muscle (50, 62), and liver (41), thereby modulating insulin secretion and sensitivity (30,41,42,50,62,66). Centrally, leptin traverses the blood-brain barrier via receptor-mediated transcytosis (ObRa) or, in the absence of a blood-brain barrier, directly accesses the intracellular signal-transducing long isoform of the leptin receptor (ObRb) expressed in the hypothalamus (2,6,8,54). In the hypothalamus, leptin alters the synthesis and release of key orexigenic (neuropeptide Y, agouti-related peptide) and anorexigenic (proopiomelanocortin and cocaine and amphetamine-related transcript) peptides in the adult, thereby suppressing appetite resulting in anorexia, increasing sympathetic nervous output resulting in enhanced energy expenditure, and ultimately producing weight loss (16,46,61).Although most of the studies involving leptin action have been reported in the adult, some information during the postnatal period exists. Circulating leptin concentrations peak in the suckling mouse at age 7-10 days and ...

Litter Size Variation in Hypothalamic Gene Expression Determines Adult Metabolic Phenotype in Brandt's Voles (Lasiopodomys brandtii)

“…Similarly, this same phenomenon is observed in human studies with hyperleptinemia in infants from gestational undernutritioned or diabetic mothers [48]. Further, intracerebroventricular leptin administration to neonatal rats altered adult female phenotypes, including a reduction in body mass and food intake [49]. These studies suggest that perinatal leptin plays the critical role in programming adult metabolic phenotypes although serum leptin showed different responses to early nutritional environments.…”

Neonatal Programming of Neuroimmunomodulation – Role of Adipocytokines and Neuropeptides

“…Similar effects were observed when leptin was injected intracerebroventricularly, associated with glucose intolerance in females [65] . In the same way, hyperinsulinemia and lower adiponectinemia were found in adult offspring whose mothers had prolactin inhibition during the last 3 days of lactation [32] .…”

“…However, they did not display higher fat depots and this could be better understood considering that they presented thyroid hyperfunction [62,63] and higher catecholamine secretion [64] as will be discussed later. Those effects seems to depend on the administration route, since Varma et al [65], who injected leptin intracerebroventricularly, observed a programming effect with lower body weight and food intake, hypoleptinemia, hyperinsulinism and an impaired glucose tolerance test but only in females. We think that our model provides a better reproduction of the increase in leptin that occurs in obesity or by leptin transfer into the milk since the increase occurs peripherally and can modulate leptin receptors.…”

Programming of hypothalamic neuropeptide gene expression in rats by maternal dietary protein content during pregnancy and lactation

“…We demonstrated that the serum concentration of leptin was altered by manipulation of maternal protein intake. Leptin during the lactation period is a candidate for programming of the appetite system [11,25,26]. Postnatal low protein animals had substantially reduced blood leptin concentration compared with control animals under both fed and fasted conditions.…”