Role of leptin-mediated PI3 Kinase signaling on reproductive control

瘦素介导的 PI3 激酶信号在生殖控制中的作用

• 批准号: 8324895
• 负责人: Carol Fuzeti Elias
• 金额: $ 6.58万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-11-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324895
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adipocytes; Adolescent; Affect; Alleles; Amenorrhea; Animals; Anorexia; Appetite Depressants; Area; Attention; Bilateral; Body Composition; Body Weight; Body Weight decreased; Brain; Cachexia; Catalytic Domain; Cell Nucleus; Collection; Cues; Cytokine Receptors; Data; Development; Diabetes Mellitus; Diestrus; Eating; Estradiol; Estrogens; Estrous Cycle; Estrus; Family; Fasting; Female; Fertility; Fertility Rates; Frequencies; Functional disorder; Genes; Gonadal Steroid Hormones; Gonadal structure; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Health; Hormones; Human; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Infertility; Knockout Mice; Knowledge; Leptin; Lesion; Link; Maintenance; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Modeling; Monitor; Mus; Neurons; Nutritional; Obesity; Ovarian; Pattern; Periodicity; Phenotype; Phosphorylation; Physiologic pulse; Pituitary Gland; Play; Proestrus; Protein Isoforms; Protein Tyrosine Kinase; Puberty; Recruitment Activity; Regulatory Element; Reproduction; Reproductive Physiology; Resistance; Role; STAT3 gene; Sexual Maturation; Signal Pathway; Signal Transduction; Site; System; Testing; Time; Transgenic Mice; Vagina; Weaning; Weight Gain; db/db mouse; design; diabetic; energy balance; excessive exercise; hormone therapy; improved; kinase inhibitor; leptin receptor; male; obesity in children; receptor expression; recombinase; reproductive; reproductive axis; reproductive function; research study; response; restoration

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.

描述（由申请人提供）：瘦素对生殖功能的作用已得到充分证实。瘦素缺乏（ob/ob）或抗性（db/db）的小鼠是不育的，对ob/ob小鼠施用瘦素（但不单独减轻体重）可以恢复其生育能力。对缺乏瘦素的肥胖儿童进行的研究支持了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。瘦素还能减弱禁食引起的 LH 分泌和生育能力的抑制。对于厌食症女性以及因一段时期体重减轻而导致下丘脑闭经的女性，瘦素治疗可增加脉搏频率和 LH 平均水平、卵巢体积、优势卵泡数量和雌二醇水平。瘦素受体 (LepR) 在大脑、垂体和性腺中表达。 LepR 在 db/db 小鼠或 LepRs 缺失小鼠大脑中的表达可完全恢复雄性和部分雌性的生育能力，表明大脑发挥着重要作用。我们发现LepR在腹侧前乳头核（PMV）中选择性地重新表达可诱导青春期、性成熟并提高生育能力。已经清楚地证明，LepRs 的长亚型通过酪氨酸激酶的 JAK 家族以及随后的 STAT3 磷酸化介导细胞信号传导。 LepR 介导的 STAT3 信号传导 (LRbS1138 s/s) 的缺失会重现 db/db 代谢表型，从而产生贪食性肥胖和糖尿病。然而值得注意的是，db/db 小鼠不育，而 LRbS1138 s/s 小鼠具有生育能力，这表明瘦素调节生殖的作用是通过不依赖 JAK/STAT3 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) 信号通路作为下丘脑神经元瘦素效应调节剂的作用。因此，我们假设 PMV 中的 PI3K 信号传导是瘦素对青春期和协调生殖控制的作用所必需的。本应用程序中提供的研究旨在直接测试该模型的组件。公共健康相关性：本研究中提出的实验旨在研究磷脂酰肌醇 3-激酶 (PI3K) 信号通路介导瘦素对生殖作用的作用。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来调节女性生殖生理学的许多参数的知识。在人类中，厌食症、恶病质和过度运动等能量负平衡状态都会减少促性腺激素的分泌，导致周期性异常和不孕。肥胖和糖尿病也会对生育能力产生负面影响。因此，希望我们的研究能够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。