Neural basis of leptin action on reproduction

瘦素对生殖作用的神经基础

• 批准号: 8606636
• 负责人: Carol Fuzeti Elias
• 金额: $ 5.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606636
• 关键词: Neural; basis; leptin; action; reproduction

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.

描述（由申请人提供）：瘦素对生殖功能的作用已得到证实。瘦素缺乏（ob/ob）或抵抗（db/db）的小鼠和人类不育，给瘦素缺乏的受试者服用瘦素可恢复其生育能力。在瘦素缺乏的肥胖儿童中进行的研究支持了瘦素对生殖生理的重要性。瘦素治疗后，观察到促性腺激素和雌二醇水平逐渐增加，性腺增大和青春期发育。瘦素还能减弱禁食引起的LH分泌抑制。在厌食的女性和那些由于体重减轻而导致下丘脑闭经的女性中，瘦素治疗增加了脉搏频率和LH平均水平、卵巢体积、显性卵泡数量和雌二醇水平。瘦素受体（LepR）在大脑、脑垂体和性腺中表达。在老鼠的大脑中表达LepR可以恢复生育能力，这表明大脑在其中起了主要作用。然而，瘦素在生殖功能中发挥作用的具体大脑部位仍未确定。近年来，kisspeptin （Kiss1基因的产物）及其受体（Kiss1r）在调节生殖中的作用逐渐明确。Kiss1或Kiss1r基因的缺失会导致性腺功能减退、性成熟异常、性类固醇和促性腺激素循环水平降低。弓形核中的Kiss1神经元子集表达LepR，与野生型相比，瘦素缺乏的ob/ob雄性小鼠显示Kiss1的表达降低。我们最近的研究表明，在禁食期间，瘦素的作用需要腹侧乳头前核（PMV）中的神经元来诱导LH分泌。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，Kiss1或PMV神经元是否传递瘦素在青春期启动和协调生殖控制中的作用尚未得到直接测试。本研究的具体目的是确定在PMV神经元（Aim1）或Kiss1神经元（Aim2）中选择性的瘦素信号传导是否足以介导瘦素在青春期开始和生殖神经内分泌轴中的允许作用。此外，我们还将评估（PMV和Kiss1）神经元群（Aim3）中瘦素信号的需求，以充分挽救LepR缺失小鼠的不育表型。