Abstract
BackgroundMaternal deprivation (MD) during neonatal life can have long-term effects on metabolism and behavior, with males and females responding differently. We previously reported that MD during 24 h at postnatal day (PND) 9 blocks the physiological neonatal leptin surge in both sexes. It is known that modifications in neonatal leptin levels can affect metabolism in adulthood. Thus, we hypothesized that at least some of the long-term metabolic changes that occur in response to MD are due to the decline in serum leptin during this critical period of development. Hence, we predicted that treatment with leptin during MD would normalize these metabolic changes, with this response also differing between the sexes.MethodsMD was carried-out in Wistar rats for 24 h on PND9. Control and MD rats of both sexes were treated from PND 9 to 13 with leptin (3 mg/kg/day sc) or vehicle. Weight gain, food intake, glucose tolerance, and pubertal onset were monitored. Sexual behavior was analyzed in males. Rats were killed at PND90, and serum hormones and hypothalamic neuropeptides involved in metabolic control and reproduction were measured. Results were analyzed by three-way analysis of covariance using sex, MD, and leptin treatment as factors and litter as the covariate and employing repeated measures where appropriate.ResultsIn males, MD advanced the external signs of puberty and increased serum insulin and triglyceride levels and hypothalamic proopiomelanocortin mRNA levels at PND90. Neonatal leptin treatment normalized these effects. In contrast, MD decreased circulating triglycerides, as well as estradiol levels, in females at PND90 and these changes were also normalized by neonatal leptin treatment. Neonatal leptin treatment also had long-term effects in control rats as it advanced the external signs of puberty in control males, but delayed them in females. Neonatal leptin treatment increased serum insulin and hypothalamic mRNA levels of the leptin receptor and cocaine- and amphetamine-regulated transcript in control males and increased orexin mRNA levels in controls of both sexes. Although pubertal onset in males was advanced by either MD or neonatal leptin treatment in males and delayed by leptin treatment in females, the mRNA levels of hypothalamic neuropeptides and receptors related to reproduction were not affected by MD or neonatal leptin treatment in either sex at PND90.ConclusionsThese findings indicate that some of the long-term changes in metabolic and reproductive parameters induced by MD, such as advanced pubertal onset and increased hypothalamic proopiomelanocortin (POMC) expression, hyperinsulinemia, and hypertriglyceridemia in adult males and decreased serum triglyceride and estradiol levels in females, are most likely due to the decrease in leptin levels during the period of MD.
Highlights
Maternal deprivation (MD) during neonatal life can have long-term effects on metabolism and behavior, with males and females responding differently
Mela et al Biology of Sex Differences (2016) 7:2 (Continued from previous page). These findings indicate that some of the long-term changes in metabolic and reproductive parameters induced by maternal deprivation (MD), such as advanced pubertal onset and increased hypothalamic proopiomelanocortin (POMC) expression, hyperinsulinemia, and hypertriglyceridemia in adult males and decreased serum triglyceride and estradiol levels in females, are most likely due to the decrease in leptin levels during the period of MD
The aims of this study were to: (1) delineate which of the previously described long-term metabolic/neuroendocrine effects of MD result from the MD-induced decline in circulating leptin levels; (2) determine if the MD procedure modifies the reproductive axis including the timing of pubertal onset, expression of gonadotrophins and neuropeptides involved in reproduction in the adult rat and male sexual behavior; (3) analyze whether the effects of MD on the reproductive axis are due to the reduction in circulating leptin levels that occurs during this procedure; (4) determine if males and females respond to these experimental manipulations
Summary
Maternal deprivation (MD) during neonatal life can have long-term effects on metabolism and behavior, with males and females responding differently. As hypothalamic development in rodents is not complete until the adolescent period, early environmental stress could disrupt the maturation of this brain region, which coordinates and controls endocrine systems [5]. This aberrant development could in turn induce long-term effects on metabolism and other neuroendocrine systems. An adipokine produced mainly by adipocytes, is involved in postnatal metabolic control [8,9,10] It has been implicated in hypothalamic development, as well as synaptic plasticity, neurogenesis, and neuronal and glial survival in diverse brain areas [6, 7, 10, 11]. Leptin is involved in reproductive function [15, 16], but the long-term effects of changes in the neonatal leptin surge on this system are less well studied
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