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建立。小鼠和人类缺乏（OB/OB）或耐药性（DB/DB）对瘦素不育，瘦素缺乏瘦素的受试者恢复了其生育能力。在缺乏瘦素的肥胖儿童中进行的研究支持了瘦素对生殖生理的重要性。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。瘦素还钝化了禁食引起的LH分泌的抑制。在厌食症的女性中，以及下丘脑闭经的患者，由于体重增加的时期增加，瘦素治疗增加了脉搏频率和平均水平，卵巢量，主要卵泡的数量和雌二醇水平。瘦素受体（LEPR）在大脑，垂体和性腺中表达。 LEPR在小鼠大脑中的表达否则为LEPR恢复了生育能力，这表明大脑起着主要作用。但是，瘦素作用在生殖功能中发挥作用的特定大脑部位仍未解决。最近，Kisspeptin（Kiss1基因的产物）及其受体（KISS1R）在调节繁殖中所扮演的角色已经变得很清楚。 KISS1或KISS1R基因的删除导致性行为，性成熟异常，性类固醇和促性腺激素的循环水平降低。弧形核中的一个KISS1神经元的子集表达LEPR，与野生类型相比，缺乏瘦素的ob/ob雄性小鼠的kiss1表达降低。我们最近表明，在禁食期间，瘦素作用诱导LH分泌需要腹侧前核核（PMV）中的神经元。 PMV表达了密集的瘦素反应神经元，并向与生殖控制有关的区域进行了项目。但是，KISS1还是PMV神经元中继瘦素对青春期起始和协调生殖控制的影响尚未直接测试。该提案的具体目的旨在确定PMV神经元（AIM1）或KISS1神经元（AIM2）中的瘦素信号是否足以介导瘦素在青春期和生殖神经内分泌轴开始中的允许作用。此外，我们还将评估（PMV和KISS1）神经元种群（AIM3）对LEPR NULL小鼠的不育表型的全部营救中的瘦素信号传导的要求。 公共卫生相关性：在人类中，像厌食症一样，卡赫西亚和过度运动的负能量平衡状态都可以降低促性腺激素的分泌，从而导致循环异常和不育。另一方面，肥胖和糖尿病也会对生育能力产生负面影响。这项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衍生的激素瘦素在生殖生理学中的作用。希望我们的研究能够为理解和进一步治疗由代谢功能障碍引起的生殖缺陷提供新的新方面。