Role of leptin-mediated PI3 Kinase signaling on reproductive control

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。瘦素缺乏（ob/ob）或抵抗（db/db）的小鼠是不育的，瘦素给药于ob/ob小鼠，而不仅仅是体重减轻，恢复了它们的生育能力。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。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分泌和生育力抑制。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。在db/db小鼠或LepRs无效的小鼠的脑中LepR的表达完全恢复雄性和部分恢复雌性的生育能力，表明脑起主要作用。我们已经发现LepR选择性地在腹侧乳头体前核（PMV）重新表达，诱导青春期，性成熟和提高生育能力。已经清楚地证明，LepRs的长同种型通过酪氨酸激酶的JAK家族和随后的STAT 3磷酸化介导细胞信号传导。LepR介导的STAT 3信号转导（LRbS 1138 s/s）的缺失重现了db/db代谢表型，产生了摄食过多性肥胖和糖尿病。然而，值得注意的是，db/db小鼠是不育的，而LRbS 1138 s/s小鼠是可生育的，这表明瘦素调节生殖的作用是通过JAK/STAT 3非依赖性信号通路发挥的。近年来，人们特别关注磷脂酰肌醇3-激酶（PI 3 K）信号通路作为下丘脑神经元中瘦素效应的介导者的作用。因此，我们假设PMV中的PI 3 K信号通路是瘦素对青春期和协调生殖控制的作用所必需的。本申请中提供的研究旨在直接测试该模型的组件。公共卫生相关性：本研究旨在探讨磷脂酰肌醇3-激酶（PI 3 K）信号通路介导瘦素对生殖的作用。这些研究旨在更好地了解脂肪细胞源性激素瘦素在生殖控制中的作用。我们的主要目标是增加关于大脑如何整合营养线索以调节女性生殖生理学的许多参数的知识。在人类中，如厌食、恶病质和过度运动的负能量平衡状态都可以减少促性腺激素分泌，导致异常的周期性和不育。肥胖和糖尿病也会对生育能力产生负面影响。因此，希望我们的研究可以为理解和进一步治疗代谢功能障碍引起的生殖缺陷开辟新的战线。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The experiments proposed in this study were designed to investigate the role played by the phosphatidylinositol 3-kinase (PI3K) signaling pathways mediating leptin action on reproduction. These studies were proposed to better understand the role of the adipocyte-derived hormone leptin in reproductive control. Our main objective is to add knowledge on how the brain integrates nutritional cues to regulate many parameters of the female reproductive physiology. In humans, states of negative energy balance as in anorexia, cachexia, and excessive exercise can all decrease gonadotropins secretion resulting in abnormal cyclicity and infertility. Obesity and diabetes can also negatively affect fertility. Thus, it is hoped that our studies may open new fronts for the understanding and for further treatment of reproductive deficits caused by metabolic dysfunctions.