Role of leptin-mediated PI3 Kinase signaling on reproductive control

描述(由申请人提供)：瘦素对生殖功能的作用是明确的。对瘦素缺乏(ob/ob)或抵抗(db/db)的小鼠是不育的，给ob/ob小鼠服用瘦素，但不是单独减肥，可以恢复它们的生育能力。在瘦素缺乏的肥胖儿童中进行的研究支持了瘦素对生育的重要性。瘦素治疗后，促性腺激素和雌二醇水平逐渐升高，性腺增大和青春期发育。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。在厌食症女性和因体重增加而导致下丘脑闭经的女性中，瘦素治疗增加了脉冲频率和平均水平的黄体生成素、卵巢体积、优势卵泡数量和雌二醇水平。瘦素受体(Lepr)表达于脑、脑下垂体腺和性腺。在db/db小鼠或LepRs为空的小鼠的大脑中，Lepr的表达完全恢复了男性的生育能力，部分恢复了女性的生育能力，这表明大脑发挥了主要作用。我们发现，LepR选择性地在腹侧乳头体前核(PMV)重新表达可诱导青春期、性成熟和提高生育力。已经清楚地证明，LepRs的长亚型通过JAK家族的酪氨酸激酶和随后的STAT3的磷酸化来介导细胞信号转导。LepR介导的STAT3信号的缺失(LRbS1138 S/S)概括了db/db的代谢表型，产生了高血压性肥胖和糖尿病。然而，值得注意的是，尽管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不依赖的信号通路发挥的。最近，磷脂酰肌醇3-激酶(PI3K)信号通路作为瘦素在下丘脑神经元中的中介作用受到了特别关注，因此，我们推测PMV中的PI3K信号是瘦素在青春期和协调生殖控制中所必需的。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：本研究中提出的实验旨在调查磷脂酰肌醇3-激酶(PI3K)信号通路在介导瘦素对生殖作用中所起的作用。这些研究是为了更好地了解脂肪细胞衍生的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来调节女性生殖生理的许多参数的知识。在人类中，能量负平衡的状态，如厌食症、恶病质和过度运动，都会减少促性腺激素的分泌，导致异常的周期性和不孕症。肥胖和糖尿病也会对生育产生负面影响。因此，我们的研究有望为理解和进一步治疗由代谢功能障碍引起的生殖缺陷开辟新的前沿。

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.