Regulatory roles of leptin in reproduction and metabolism: a comparative review.
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Leptin plays an important role in signaling nutritional status to the central reproductive axis of mammals and appears to be at least a permissive factor in the initiation of puberty. The expression and secretion of leptin are correlated with body fat mass and are acutely affected by changes in feed intake. Moreover, circulating leptin increases during pubertal development in rodents, human females and heifers. Effects of leptin are mediated mainly via receptor activation of the JAK-STAT pathway; however, activation of alternative pathways, such as MAP kinase, has also been reported. Although the leptin receptor (LR) has not been found on GnRH neurons, leptin stimulates the release of GnRH from rat and porcine hypothalamic explants. Moreover, leptin increases the release of LH in rats and from adenohypophyseal explants and/or cells from full-fed rats and pigs. In contrast, stimulation of the hypothalamic-gonadotropic axis by leptin in cattle and sheep is observed predominantly in animals and tissues pre-exposed to profound negative energy balance. For example, leptin prevents fasting-mediated reductions in the frequency of LH pulses in peripubertal heifers, augments the magnitude of LH and GnRH pulses in fasted cows, and enhances basal secretion of LH in vivo and from adenohypophyseal explants of fasted cows. However, leptin is incapable of accelerating the frequency of LH pulses in prepubertal heifers, regardless of nutrient status, and has no effect on the secretion of GnRH and LH in full-fed cattle or hypothalamic/hypophyseal explants derived thereof. Similar to results obtained with LH, basal secretion of GH from anterior pituitary explants of fasted, but not normal-fed cows, was potentiated acutely by low, but not high, doses of leptin. Mechanisms through which undernutrition hypersensitize the hypothalamic-gonadotropic axis to leptin may involve up-regulation of the LR. However, an increase in LR mRNA expression is not a requisite feature of heightened adenohypophyseal responses in fasted cattle. To date, leptin has not been successful for inducing puberty in ruminants. Future therapeutic uses for recombinant leptin that exploit states of nutritional hypersensitization, and identification of genetic markers for genotypic variation in leptin resistance, are currently under investigation.
