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

基本信息

批准号：
7696426
负责人：
Carol Fuzeti Elias
金额：
$ 32.58万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7696426
关键词：
1-Phosphatidylinositol 3-Kinase Adipocytes Adolescent Affect Amenorrhea Animals Anorexia Anteroventral Thalamic Nucleus Appetite Depressants Area Attention Bilateral Body Weight decreased Brain Cachexia Catalytic Domain Cell Nucleus Child Collection Cues Cytokine Receptors Data Development Diabetes Mellitus Diestrus Estradiol Estrogens Estrous Cycle Estrus Family Fasting Female Fertility Frequencies Functional disorder Gonadal Steroid Hormones Gonadal structure Gonadotropin Hormone Releasing Hormone Gonadotropins Hormones Human Hypothalamic structure Immunohistochemistry In Situ Hybridization Infertility Knockout Mice Knowledge Leptin Lesion Maintenance Mediating Mediator of activation protein Messenger RNA Metabolic Modeling Monitor Mus Neurons Nutritional Obesity Ovarian 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 leptin receptor male public health relevance receptor expression recombinase reproductive reproductive axis reproductive function research study response restoration

项目摘要

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.

项目概要/摘要瘦素对生殖功能的作用已得到充分证实。小鼠缺陷（ob/ob）或耐药 (db/db)给瘦素是不育的，给ob/ob小鼠施用瘦素，但不能单独减肥，恢复他们的生育能力。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，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。瘦素还可以减弱禁食引起的 LH 分泌和生育能力的抑制。在厌食症女性中，那些因一段时期体重减轻、瘦素增加而导致下丘脑闭经的人治疗增加脉冲频率和 LH 平均水平、卵巢体积、显性卵泡数量卵泡和雌二醇水平。瘦素受体 (LepR) 在大脑、垂体和性腺。 db/db 小鼠大脑中 LepR 的表达或 LepR 恢复无效的小鼠男性完全具有生育能力，女性部分具有生育能力，这表明大脑发挥着重要作用。我们发现LepR选择性地在腹侧前乳头核中重新表达 (PMV) 诱导青春期、性成熟并提高生育能力。已经清楚地证明了 LepRs 的长亚型通过酪氨酸激酶 JAK 家族介导细胞信号传导随后 STAT3 磷酸化。 LepR 介导的 STAT3 信号传导 (LRbS1138 s/s) 概括了 db/db 代谢表型，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 的信号传导发挥的途径。最近，人们特别关注磷脂酰肌醇3-激酶的作用（PI3K）信号通路作为下丘脑神经元瘦素效应的介质因此，我们假设 PMV 中的 PI3K 信号传导是瘦素对青春期的影响所必需的，协调的生殖控制。本申请中提供的研究旨在直接测试该模型的组件。