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: 7993025
• 负责人: Martin Jeffrey Kelly
• 金额: $ 47.83万
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993025
• 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; Gonadotropins; 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. PUBLIC HEALTH RELEVANCE: Excessive exercise, eating disorders or weight loss in women can cause amenorrhea, which is characterized by low levels of serum 17-estradiol and anovulation. It is known that during negative energy balance the hormone leptin that is released from fat stores is drastically reduced and may contribute to hypothalamic amenorrhea conditions. However, leptin receptors are not expressed in hypothalamic gonadotropin releasing hormone (GnRH) neurons, which are directly responsible for the control of the ovulatory cycle, but in kisspeptin neurons that are essential for the excitatory input to GnRH neurons. Therefore, the current studies will characterize the cross-talk between leptin and 17-estradiol signaling in kisspeptin neurons in fed and fasted states. Understanding the convergence of leptin and estrogen 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(申请人提供)：该项目的主要目标是阐明瘦素和17-雌二醇之间的信号在Kispeptin神经元之间的串扰。先天性瘦素缺乏和/或由于瘦素突变导致的瘦素功能丧失可导致肥胖和性腺激素减退症。应用瘦素可以逆转下丘脑性腺功能减退及其相关的紊乱。瘦素通过其同源受体瘦素受体(LRs)传递信号。长异构体(LRB)是该受体的主要信号形式，在下丘脑神经元中大量表达，包括弓状原阿片黑素皮质素(POMC)和Kispeptin神经元，而促性腺激素释放激素(GnRH)神经元不表达。因此，瘦素对GnRH神经元的作用被认为是通过神经元与GnRH神经元的突触间接介导的。下丘脑Kispeptin神经元在调节GnRH的释放从而控制生殖方面起着关键作用。此外，肥胖和不育ob/ob小鼠的Kiss1mRNA水平降低，而瘦素治疗后Kiss1mRNA水平升高。此外，17-雌二醇(17-estadiol，E_2)对Kiss1mRNA和Kis-speptin蛋白的表达有高度的调节作用，最近我们发现E_2对雌性豚鼠弓形Kis-speptin神经元有不同的调节作用，在负反馈时抑制表达，在正反馈时增强表达。此外，我们还发现，瘦素通过一种新的信号通路使POMC神经元去极化，该信号通路与规范瞬时受体电位(TRPC)通道的激活相耦合，Kispeptin神经元可能也受到类似的调节。因此，我们目前的工作主要集中在下丘脑弓状核Kispeptin神经元以及E2和Leptin之间的相互作用，这些相互作用通过多个信号级联作用来影响Kispeptin神经元的兴奋性，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，Kispeptin神经元是雌性GnRH神经元兴奋性驱动的守门人，正是这些神经元中E2和瘦素的复杂相互作用控制了进食和禁食状态下的排卵周期。因此，本研究的具体目的如下：(1)研究去卵巢雌性豚鼠弓状核Kispeptin神经元中瘦素信号转导途径。(2)研究正反馈与负反馈对弓状体结蛋白神经元的影响。(3)探讨E_2对禁食和喂食豚鼠正反馈过程中弓状体结蛋白神经元的作用。(4)探讨雌激素和禁食对Kispeptin神经元K-ATP通道表达的影响。了解瘦素和E2信号在弓状Kispeptin神经元中的汇聚，将有助于深入了解这些激素在将代谢信号传递到生殖轴方面的基础作用。 公共卫生相关性：女性过度运动、饮食失调或体重减轻可导致闭经，其特征是血清17-雌二醇水平低和无排卵。众所周知，在负能量平衡期间，从脂肪储存中释放的瘦素荷尔蒙会急剧减少，可能会导致下丘脑闭经。然而，瘦素受体不表达于直接控制排卵周期的下丘脑促性腺激素释放激素(GnRH)神经元，而表达于对GnRH神经元的兴奋性输入至关重要的Kispeptin神经元。因此，目前的研究将描述在进食和禁食状态下Kispeptin神经元中瘦素和17-雌二醇信号之间的串扰。了解瘦素和雌激素信号在弓状Kispeptin神经元中的汇聚，将有助于深入了解这些激素在将代谢信号传递到生殖轴方面的基础作用。