Leptin's actions on the reproductive axis: perspectives and mechanisms

Energy availability influences reproductive fitness. The activity of the reproductive axis is sensitive to the adequacy of nutrition and the stores of metabolic reserves. The adipocyte-derived hormone leptin is postulated to reflect the state of nutrition and energy reserves and serve as a metabolic gate to the reproductive system. Genetically obese ob/ob mice (lacking endogenous leptin) are infertile, and treatment of these animals with exogenous leptin stimulates the activity of the reproductive endocrine system and induces fertility in both sexes. Severely food-restricted animals have reduced circulating levels of leptin, which are associated with markedly reduced secretion of the gonadotropins, LH, and FSH. Treatment of food-restricted mice, rats, sheep, and monkeys with exogenous leptin reverses the diet-induced inhibition of gonadotropin secretion. Leptin has also been suggested to have a role in timing the onset of puberty in several species, although evidence that leptin is the primary metabolic signal for initiating the onset of puberty in any species is controversial. Notwithstanding this debate, it is undisputed for all species studied to date that adequate levels of leptin in the circulation are essential (but not sufficient) for pubertal progression and that leptin treatment can reverse the delay in sexual maturation caused by food restriction. Double-label in situ hybridization studies in the brain of the mouse, rat, and monkey have revealed that hypothalamic neurons expressing proopiomelanocortin and neuropeptide Y coexpress the leptin receptor, whereas no evidence has been adduced that GnRH neurons express this receptor. Together, these observations suggest that leptin is a metabolic signal to the neuroendocrine reproductive system and that under conditions of inadequate energy reserves, low leptin levels act as a metabolic "gate" to inhibit the activity of the neuroendocrine reproductive axis in both sexes.