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已得到证实。瘦素缺乏（ob/ob）或抵抗（db/db）的小鼠都是不育的，给瘦素治疗ob/ob小鼠，而不是单独减肥，可以恢复它们的生育能力。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，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。瘦素还能减弱禁食对LH分泌和生育能力的抑制。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db/db小鼠或其他没有LepR的小鼠的大脑中，LepR的表达在雄性中完全恢复了生育能力，在雌性中部分恢复了生育能力，这表明大脑发挥了主要作用。我们发现LepR在腹侧乳头前核（PMV）选择性地重新表达，诱导青春期、性成熟和提高生育能力。已经清楚地证明，LepRs的长亚型通过酪氨酸激酶的JAK家族和随后的STAT3磷酸化介导细胞信号传导。lepr介导的STAT3信号（LRbS1138 s/s）的缺失再现了db/db代谢表型，产生肥厚性肥胖和糖尿病。然而，值得注意的是，db/db小鼠是不育的，而LRbS1138 s/s小鼠是可育的，这表明瘦素调节生殖的作用是通过JAK/ stat3独立的信号通路发挥的。最近，人们特别关注磷脂酰肌醇3-激酶（PI3K）信号通路在下丘脑神经元中作为瘦素作用的中介的作用，因此，我们假设PMV中的PI3K信号通路是瘦素在青春期和协调生殖控制中的作用所必需的。本应用程序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：本研究提出的实验旨在探讨磷脂酰肌醇3-激酶（PI3K）信号通路介导瘦素对生殖的作用。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，厌食症、恶病质和过度运动等负能量平衡状态都可以减少促性腺激素的分泌，导致周期异常和不孕。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.