Neural basis of leptin action on reproduction

性状（由申请方提供）：瘦素对生殖功能的作用已得到充分证实。小鼠和人类缺乏（ob/ob）或抵抗（db/db）瘦素是不育的，瘦素缺乏的受试者和瘦素管理恢复他们的生育能力。在肥胖儿童缺乏瘦素的研究支持瘦素对生殖生理的重要性。瘦素治疗后，促性腺激素和雌二醇水平逐渐增加，性腺和青春期发育的扩大进行了观察。瘦素还减弱了禁食诱导的LH分泌抑制。在厌食症女性，和那些下丘脑闭经导致一段时间的体重下降，瘦素治疗增加脉冲频率和LH的平均水平，卵巢体积，优势卵泡数和雌二醇水平。瘦素受体（Leptin receptor，LepR）在脑、垂体和性腺中均有表达。LepR在小鼠脑中的表达，否则LepR无效，恢复生育能力，表明大脑起着重要作用。然而，瘦素在生殖功能中发挥作用的具体脑部位仍不清楚。近年来，Kiss 1基因产物kisspeptin及其受体Kiss 1 r在生殖调控中的作用逐渐被人们所认识。Kiss 1或Kiss 1 r基因缺失导致性腺功能减退、性成熟异常和性类固醇和促性腺激素循环水平降低。弓状核中Kiss 1神经元的一个子集表达LepR，与野生型相比，瘦素缺乏的ob/ob雄性小鼠Kiss 1表达减少。我们最近发现，腹前乳头体核（PMV）的神经元所需的瘦素行动，以诱导LH分泌在禁食期间。PMV表达瘦素反应神经元的密集集合，并投射到与生殖控制相关的区域。然而，Kiss 1或PMV神经元是否中继瘦素对青春期启动和协调生殖控制的影响尚未得到直接测试。这个建议的具体目的是确定是否瘦素信号选择性PMV神经元（Aim 1）或Kiss 1神经元（Aim 2）是足以介导瘦素的许可效应在青春期的开始和生殖神经内分泌轴。此外，我们还将评估两种（PMV和Kiss 1）神经元群体（Aim 3）中瘦素信号传导的需求，以完全拯救LepR缺失小鼠的不育表型。

DESCRIPTION (provided by applicant: Leptin action on reproductive functions is well established. Mice and humans deficient (ob/ob) or resistant (db/db) to leptin are infertile, and leptin administration to leptin-deficient subjects restore their fertility. Studies conducted in obese children deficient in leptin have supported the importance of leptin to reproductive physiology. Following leptin treatment, a gradual increase in gonadotropins and estradiol levels, enlargement of the gonads and pubertal development were observed. Leptin also blunts the fasting-induced suppression of LH secretion. In anorectic females, and those with hypothalamic amenorrhea resulting from a period of increased weight lost, leptin treatment increased pulse frequency and mean levels of LH, ovarian volume, number of dominant follicles and estradiol levels. Leptin receptors (LepR) are expressed in brain, pituitary gland and gonads. Expression of LepR in the brain of mice otherwise null for LepRs restores fertility suggesting that the brain plays a major role. However, the specific brain sites where leptin acts to exert its effect in the reproductive function is still unsettled. Recently, the role played by kisspeptin (product of Kiss1 gene) and its receptor (Kiss1r) in regulating reproduction has become clear. Deletion of Kiss1 or Kiss1r genes results in hypogonadism, abnormal sexual maturation and decreased circulating levels of sex steroids and gonadotropins. A subset of Kiss1 neurons in the arcuate nucleus expresses LepR, and compared to wild types, leptin-deficient ob/ob male mice show decreased expression of Kiss1. We have recently shown that neurons in the ventral premammillary nucleus (PMV) are required for leptin action to induce LH secretion during fasting. The PMV express a dense collection of leptin responsive neurons and project to areas related to reproductive control. However, whether Kiss1 or PMV neurons relay leptin's effect on puberty initiation and coordinated reproductive control has not been directly test. The specific aims of this proposal are designed to determine whether leptin signaling selectively in PMV neurons (Aim1) or in Kiss1 neurons (Aim2) is sufficient to mediate leptin's permissive effect in the onset of puberty and in the reproductive neuroendocrine axis. In addition, we will also assess the requirement of leptin signaling in both (PMV and Kiss1) neuronal population (Aim3) for the full rescue of the infertility phenotype of LepR null mice.