Role of leptin-mediated PI3 Kinase signaling on reproductive control

项目总结/摘要 瘦素对生殖功能的作用已得到充分证实。缺乏（ob/ob）或耐药小鼠 (db/db）对瘦素的作用是不育的，而瘦素对ob/ob小鼠的给药，但不是单独的体重减轻， 恢复生育能力在缺乏瘦素的肥胖儿童中进行的研究支持了 瘦素对生育的重要性瘦素治疗后，促性腺激素水平逐渐升高， 观察雌激素水平、性腺增大和青春期发育情况。瘦素 也减弱了禁食诱导的LH分泌和生育力抑制。在厌食症女性中， 那些由于体重减轻、瘦素增加而导致下丘脑性闭经的患者 治疗增加了脉冲频率和LH的平均水平，卵巢体积，显性 卵泡和雌二醇水平。瘦素受体（LepR）在脑、脑垂体和垂体中表达。 生殖腺db/db小鼠或其他LepRs缺失小鼠脑中LepR的表达恢复 男性的生育能力完全下降，女性的生育能力部分下降，这表明大脑起着重要作用。 我们发现LepR选择性地在乳头体前腹侧核表达， (PMV)诱导青春期、性成熟和提高生育能力。已经清楚地表明， LepRs的长同种型通过酪氨酸激酶的JAK家族介导细胞信号传导， 随后的STAT 3磷酸化。LepR介导的STAT 3信号转导（LRbS 1138）的缺失 s/s）再现了db/db代谢表型，产生了过度吞噬性肥胖和糖尿病。 然而，值得注意的是，db/db小鼠是不育的，而LRbS 1138 s/s小鼠是能生育的，这表明 瘦素通过JAK/STAT 3非依赖性信号途径调控生殖 途径。近年来，磷脂酰肌醇3-激酶的作用引起了人们的特别关注， （PI 3 K）信号通路作为下丘脑神经元中瘦素效应的介质 假设PMV中的PI 3 K信号传导是瘦素对青春期的影响所必需的， 协调生殖控制。本申请提供的研究旨在直接 测试该模型的组件。

PROJECT SUMMARY/ABSTRACT Leptin action on reproductive functions is well established. Mice deficient (ob/ob) or resistant (db/db) to leptin are infertile, and leptin administration to ob/ob mice, but not weight loss alone, restores their fertility. Studies conducted in obese children deficient in leptin have supported the importance of leptin to fertility. 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 and fertility. 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 db/db mice or mice otherwise null for LepRs restores fertility completely in males and partially in females, suggesting that the brain plays a major role. We have found that re-expression of LepR selectively in the ventral premammillary nucleus (PMV) induce puberty, sexual maturation and improve fertility. It has been clearly demonstrated that the long isoform of LepRs mediates cell signaling via the JAK family of tyrosine kinases and subsequent phosphorylation of STAT3. Deletion of LepR-mediated STAT3 signaling (LRbS1138 s/s) recapitulates the db/db metabolic phenotype, producing hyperphagic obesity and diabetes. Notably however, whereas db/db mice are infertile, LRbS1138 s/s mice are fertile, suggesting that the effects of leptin to regulate reproduction are exerted by JAK/STAT3-independent signaling pathways. Recently, special attention has focused on the role of phosphatidylinositol 3-kinase (PI3K) signaling pathways as mediator of leptin effects in hypothalamic neurons Therefore, we hypothesize that PI3K signaling in the PMV is required for the leptin effect on puberty and coordinated reproductive control. The studies offered in this application are designed to directly test components of this model.