Neural basis of leptin action on reproduction

瘦素对生殖作用的神经基础

• 批准号: 8238046
• 负责人: Carol Fuzeti Elias
• 金额: $ 26.95万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2012-11-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238046
• 关键词: Adipocytes; Adult; Affect; Amenorrhea; Anorexia; Appetite Depressants; Area; Bilateral; Brain; Cachexia; Cell Nucleus; Collection; Complex; Cues; Development; Diabetes Mellitus; Estradiol; Experimental Models; Fasting; Female; Fertility; Food; Frequencies; Functional disorder; Genes; Genetic; Germ Cells; Gonadal Steroid Hormones; Gonadal structure; Gonadotropins; Hormones; Human; Hypogonadism; Hypothalamic dysfunction; Hypothalamic structure; Infertility; Investigation; Knockout Mice; Lactation; Leptin; Leptin deficiency; Lesion; Life; Mediating; Menarche; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Modeling; Mus; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovarian; Pathway interactions; Periodicity; Phenotype; Physiologic pulse; Physiological; Pituitary Gland; Play; Population; Precocious Puberty; Pregnancy Maintenance; Production; Puberty; Rattus; Recovery; Reproduction; Reproductive Physiology; Reproductive system; Resistance; Risk; Rodent; Role; Sexual Maturation; Signal Transduction; Site; Steroid biosynthesis; Structure of nucleus infundibularis hypothalami; Syndrome; System; Testing; Testis; Weight Gain; Woman; base; design; energy balance; excessive exercise; girls; kisspeptin; leptin receptor; male; malignant breast neoplasm; men; mouse model; obesity in children; pubertal timing; receptor; relating to nervous system; reproductive; reproductive axis; reproductive function; reproductive hormone; research study; restoration

DESCRIPTION (provided by applicant): Leptin action on reproductive functions is well established. Mice and humans deficient (ob/ob) or resistant (db/db) to leptin are infertile, and leptin administration to leptin-deficient subjects restore their fertility. Studies conducted in obese children deficient in leptin have supported the importance of leptin to reproductive physiology. 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. 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 mice otherwise null for LepRs restores fertility suggesting that the brain plays a major role. However, the specific brain site where leptin acts to exert its effect in the reproductive function is still unsettled. Recently, the role played by kisspeptin (product of Kiss1 gene) and its receptor (Kiss1r) in regulating reproduction has become clear. Deletion of Kiss1 or Kiss1r genes results in hypogonadism, abnormal sexual maturation and decreased circulating levels of sex steroids and gonadotropins. A subset of Kiss1 neurons in the arcuate nucleus expresses LepR, and compared to wild types, leptin-deficient ob/ob male mice show decreased expression of Kiss1. We have recently shown that neurons in the ventral premammillary nucleus (PMV) are required for leptin action to induce LH secretion during fasting. The PMV express a dense collection of leptin responsive neurons and project to areas related to reproductive control. However, whether Kiss1 or PMV neurons relay leptin's effect on puberty initiation and coordinated reproductive control has not been directly test. The specific aims of this proposal are designed to determine whether leptin signaling selectively in PMV neurons (Aim1) or in Kiss1 neurons (Aim2) is sufficient to mediate leptin's permissive effect in the onset of puberty and in the reproductive neuroendocrine axis. In addition, we will also assess the requirement of leptin signaling in both (PMV and Kiss1) neuronal population (Aim3) for the full rescue of the infertility phenotype of LepR null mice. PUBLIC HEALTH RELEVANCE: 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. On the other hand, obesity and diabetes can also negatively affect fertility. The experiments proposed in this study were designed to determine the role played by hypothalamic neurons to mediate the effects of the adipocyte-derived hormone leptin in the reproductive physiology. 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）的小鼠和人类是不育的，而对瘦素缺乏的受试者施用瘦素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殖生理学的重要性。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。小鼠大脑中 LepR 的表达（否则 LepR 无效）可恢复生育能力，表明大脑发挥着重要作用。然而，瘦素在生殖功能中发挥作用的特定大脑部位仍不确定。最近，Kisspeptin（Kiss1基因的产物）及其受体（Kiss1r）在调节生殖中的作用已变得清晰。 Kiss1 或 Kiss1r 基因的缺失会导致性腺功能减退、性成熟异常以及性类固醇和促性腺激素循环水平降低。弓状核中的 Kiss1 神经元子集表达 LepR，与野生型相比，瘦素缺陷的 ob/ob 雄性小鼠的 Kiss1 表达降低。我们最近发现，禁食期间腹侧前乳头核 (PMV) 中的神经元是瘦素作用诱导 LH 分泌所必需的。 PMV 表达密集的瘦素反应神经元，并投射到与生殖控制相关的区域。然而，Kiss1 或 PMV 神经元是否传递瘦素对青春期启动和协调生殖控制的影响尚未得到直接测试。该提案的具体目的是确定 PMV 神经元 (Aim1) 或 Kiss1 神经元 (Aim2) 中选择性的瘦素信号传导是否足以介导瘦素在青春期开始和生殖神经内分泌轴中的许可作用。此外，我们还将评估（PMV 和 Kiss1）神经元群 (Aim3) 中瘦素信号传导的需求，以全面挽救 LepR 缺失小鼠的不育表型。 公共健康相关性：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。另一方面，肥胖和糖尿病也会对生育能力产生负面影响。本研究中提出的实验旨在确定下丘脑神经元在介导脂肪细胞源性激素瘦素在生殖生理学中的作用中所起的作用。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。