Cross-Talk between Leptin and Estrogen Signaling in Hypothalamic Arcuate Neurons

下丘脑弓状神经元中瘦素和雌激素信号传导之间的串扰

• 批准号: 8488293
• 负责人: Martin Jeffrey Kelly
• 金额: $ 37.93万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8488293
• 关键词: Affect; Afferent Neurons; Amenorrhea; Animals; Anovulation; Attenuated; Body Weight decreased; Cavia; Characteristics; Complex; Coupled; Cues; Eating Disorders; Electrophysiology (science); Estradiol; Estrogens; Fasting; Fatty acid glycerol esters; Feedback; Female; Goals; Gonadotropin Hormone Releasing Hormone; Growth; Histocytochemistry; Hormones; Human; Hypoglycemia; Hypogonadism; Hypothalamic structure; Infertility; Klinefelter' s Syndrome; Leptin; Leptin deficiency; Medial Dorsal Nucleus; Mediating; Messenger RNA; Metabolic; Molecular; Molecular Biology; Mutation; Neurons; Obesity; Physiology; Play; Pro-Opiomelanocortin; Protein Isoforms; Proteins; Publications; Receptor Signaling; Recombinants; Reproduction; Role; Serum; Signal Pathway; Signal Transduction; Synapses; Woman; Work; energy balance; excessive exercise; feeding; insight; interdisciplinary approach; kisspeptin; leptin receptor; neuronal excitability; novel; public health relevance; receptor; reproductive; reproductive axis; tool

DESCRIPTION (provided by applicant): The primary goal of this project is to elucidate the cross-talk between leptin and 17-estradiol signaling in kisspeptin neurons. Congenital leptin deficiency and/or loss of leptin function due to mutations in leptin can cause obesity and hypogonadotropic hypogonadism. Hypothalamic hypogonadism and its associated disturbances can be reversed by administration of leptin. Leptin signals via its cognate receptors, leptin receptors (LRs). The long isoform (LRb) is the predominant signaling form of the receptor and is abundantly expressed in hypothalamic neurons, including arcuate proopiomelanocortin (POMC) and kisspeptin neurons, but not in gonadotropin releasing-hormone (GnRH) neurons. Therefore, the effects of leptin on GnRH neurons are thought to be mediated indirectly via neurons synapsing on GnRH neurons. Hypothalamic kisspeptin neurons play a critical role in modulating GnRH release and hence the control of reproduction. Moreover, KiSS1 mRNA is reduced in obese and infertile ob/ob mice, and the levels of Kiss1 mRNA increase after administration of leptin. Furthermore, KiSS1 mRNA and kisspeptin protein are highly regulated by 17- estradiol (E2), and recently, we have found that E2 differentially regulates arcuate kisspeptin neurons in the female guinea pig, inhibiting expression during negative feedback and augmenting expression during positive feedback. In addition, we have discovered that leptin depolarizes POMC neurons via a novel signaling pathway that is coupled to activation of canonical transient receptor potential (TRPC) channels, and kisspeptin neurons may be similarly regulated. Therefore, our current work focuses on hypothalamic arcuate kisspeptin neurons and the interaction between E2 and leptin acting through multiple signaling cascades to affect kisspeptin neuronal excitability and ultimately the reproductive cycle. Our multidisciplinary approach incorporates a unique array of cellular and molecular tools and our combined expertise (electrophysiology, molecular biology, histochemistry and whole animal physiology). Our working hypothesis is that the kisspeptin neurons are the "gate-keeper" of excitatory drive to GnRH neurons in the female, and it is the complex interaction of E2 and leptin in these neurons that control the ovulatory cycle in fed and fasted states. Therefore, our specific aims are the following: (1) To characterize the leptin signaling pathway in arcuate kisspeptin neurons in ovariectomized female guinea pigs. (2) To characterize the effects of E2 on arcuate kisspeptin neurons during positive feedback versus negative feedback. (3) To elucidate the actions of E2 on arcuate kisspeptin neurons during positive feedback in fasted versus fed guinea pigs. (4) To elucidate the effects of E2 and fasting on the expression of K-ATP channels in kisspeptin neurons. Understanding the convergence of leptin and E2 signaling in arcuate kisspeptin neurons will provide insight into the fundamental role of these hormones in conveying metabolic cues to the reproductive axis.

描述（由申请人提供）：该项目的主要目标是阐明 Kisspeptin 神经元中瘦素和 17-雌二醇信号传导之间的串扰。先天性瘦素缺乏和/或由于瘦素突变导致瘦素功能丧失可导致肥胖和低促性腺激素性性腺功能减退症。下丘脑性腺功能减退及其相关的紊乱可以通过瘦素的施用来逆转。瘦素通过其同源受体瘦素受体 (LR) 发出信号。长异构体 (LRb) 是该受体的主要信号传导形式，在下丘脑神经元中大量表达，包括弓状阿片黑皮素原 (POMC) 和 Kisspeptin 神经元，但在促性腺激素释放激素 (GnRH) 神经元中不表达。因此，瘦素对 GnRH 神经元的作用被认为是通过 GnRH 神经元上的神经元突触间接介导的。下丘脑 Kisspeptin 神经元在调节 GnRH 释放从而控制生殖方面发挥着关键作用。此外，在肥胖和不育的ob/ob小鼠中，KiSS1 mRNA减少，而在施用瘦素后Kiss1 mRNA水平增加。此外，KiSS1 mRNA和Kisspeptin蛋白受到17-雌二醇（E2）的高度调节，最近，我们发现E2对雌性豚鼠的弓状Kisspeptin神经元有差异性调节，在负反馈期间抑制表达，在正反馈期间增强表达。此外，我们发现瘦素通过一种新的信号通路使 POMC 神经元去极化，该信号通路与经典瞬时受体电位 (TRPC) 通道的激活相耦合，并且 Kisspeptin 神经元可能受到类似的调节。因此，我们目前的工作重点是下丘脑弓形 Kisspeptin 神经元以及 E2 和瘦素之间的相互作用，通过多个信号级联作用影响 Kisspeptin 神经元的兴奋性并最终影响生殖周期。我们的多学科方法结合了一系列独特的细胞和分子工具以及我们的综合专业知识（电生理学、分子生物学、组织化学和整个动物生理学）。我们的工作假设是，Kisspeptin 神经元是女性 GnRH 神经元兴奋性驱动的“看门人”，这些神经元中 E2 和瘦素的复杂相互作用控制着进食和禁食状态下的排卵周期。因此，我们的具体目标如下：（1）表征去势雌性豚鼠弓形 Kisspeptin 神经元的瘦素信号通路。 (2) 表征正反馈与负反馈期间 E2 对弓形 Kisspeptin 神经元的影响。 (3) 阐明 E2 在禁食与进食豚鼠的正反馈过程中对弓形 Kisspeptin 神经元的作用。 (4)阐明E2和禁食对Kisspeptin神经元K-ATP通道表达的影响。了解弓状 Kisspeptin 神经元中瘦素和 E2 信号传导的汇聚将有助于深入了解这些激素在向生殖轴传递代谢信号方面的基本作用。