Role of leptin-mediated PI3 Kinase signaling on reproductive control

项目摘要/摘要 瘦素对生殖功能的作用是众所周知的。缺乏(ob/ob)或抵抗的小鼠 (db/db)到瘦素都是不育的，给ob/ob小鼠服用瘦素，但不只是减肥， 恢复他们的生育能力。对瘦素缺乏的肥胖儿童进行的研究支持 瘦素对生育的重要性。在瘦素治疗后，促性腺激素逐渐增加 观察雌二醇水平、性腺增大和青春期发育情况。瘦素 还可以钝化禁食导致的促黄体生成素分泌抑制和生育能力。在厌食症女性身上，以及 那些由于体重增加而导致下丘脑闭经的人，瘦素 治疗可提高脉搏频率和平均促黄体生成素水平、卵巢体积、优势数 卵泡和雌二醇水平。瘦素受体(Lepr)表达于脑、脑下垂体腺和 性腺。LepR在db/db小鼠和LepRs恢复阴性小鼠脑内的表达 男性完全有生育能力，女性有部分生育能力，这表明大脑起着主要作用。 我们发现LepR选择性地在乳头体前腹侧核重新表达 (PMV)诱导青春期、性成熟和提高生育力。它已经被清楚地证明了 LepRs的长亚型通过JAK家族的酪氨酸激酶和 随后STAT3的磷酸化。Lepr介导的STAT3信号(LRbS1138)的缺失 S/S)概括了db/db代谢表型，产生了高血压性肥胖和糖尿病。 然而，值得注意的是，db/db小鼠是不育的，而LRbS1138 S/S小鼠是可生育的，这表明 瘦素调节生殖的作用是通过JAK/STAT3非依赖性信号途径实现的 小路。最近，人们特别关注磷脂酰肌醇3-激酶的作用。 (PI3K)信号通路在下丘脑神经元中作为瘦素效应的中介，因此，我们 假设PMV中的PI3K信号是瘦素对青春期和青春期的影响所必需的 协调生殖控制。本申请中提供的研究旨在直接 测试此模型的组件。

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.