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

基本信息

批准号：
8113859
负责人：
Martin Jeffrey Kelly
金额：
$ 39.3万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8113859
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&apos 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

项目摘要

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（由申请人提供）：该项目的主要目标是阐明亲肽神经元中瘦素和17-雌二醇信号传导之间的串扰。先天性瘦素缺乏症和/或由于瘦素突变引起的瘦素功能丧失会导致肥胖和性降低性性低负症。下丘脑性不足及其相关障碍可以通过瘦素的给药来逆转。瘦素信号通过其同源受体，瘦素受体（LRS）。长同工型（LRB）是受体的主要信号传导形式，在下丘脑神经元中大量表达，包括弧形促肌蛋白酶素（POMC）和Kisspeptepin神经元，但在促性腺激素释放性激素缓解蛋白（GNRH）神经元中不表达。因此，瘦素对GNRH神经元的影响被认为是通过GNRH神经元突触的神经元间接介导的。下丘脑亲吻肽神经元在调节GNRH释放中起着关键作用，因此控制了繁殖。此外，肥胖和不育OB/OB小鼠的KISS1 mRNA减少，瘦素给药后的KISS1 mRNA水平增加。此外，KISS1 mRNA和Kisspeptin蛋白受17-雌二醇（E2）的高度调节，最近，我们发现E2在雌性豚鼠中差异调节了弧菌神经元的弧菌神经元，在阳性反馈期间抑制了负反馈和增强表达过程中的表达。此外，我们发现瘦素通过新的信号传导途径去极化POMC神经元，该途径与典型的瞬态受体电位（TRPC）通道的激活耦合，而Kisspeptepin神经元可以类似地受到调节。因此，我们当前的工作着重于下丘脑弧形亲吻肽神经元以及通过多种信号级联反应作用的E2和瘦素之间的相互作用，以影响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独特的细胞和分子工具以及我们的组合专业知识（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，亲吻蛋白神经元是雌性在雌性中GNRH神经元的兴奋性驱动的“看门人”，而这些神经元中E2和瘦素的复杂相互作用控制着美联储和禁食状态中的排卵周期。因此，我们的具体目的是：（1）表征卵巢雌性豚鼠中弧菌神经元中瘦素信号通路。（2）在正反馈与负反馈中表征E2对弧形亲吻肽神经元的影响。（3）阐明在禁食和喂豚鼠的阳性反馈期间，E2对弧菌神经元的作用。（4）阐明E2和禁食对K-ATP通道在Kisspeptin神经元中的表达。了解弓形亲吻蛋白神经元中瘦素和E2信号传导的收敛性将洞悉这些激素在将代谢线索传达到生殖轴上的基本作用。公共卫生相关性：女性的过度运动，饮食失调或体重减轻会引起闭经，其特征是血清17-雌二醇水平较低，并且缺乏。众所周知，在负能量平衡期间，从脂肪储存中释放的激素瘦素大大降低，可能有助于下丘脑闭经条件。然而，在下丘脑性促性腺激素释放激素（GNRH）神经元中，瘦素受体并未表达，这些激素（GNRH）神经元直接负责控制排卵周期，而是在kisspeptepin神经元中，这是对GNRH神经元兴奋性输入至关重要的。因此，当前的研究将表征在FED和禁食状态下的亲肽神经元中瘦素和17-雌二醇信号传导之间的串扰。了解弓形亲吻蛋白神经元中瘦素和雌激素信号传导的收敛性将洞悉这些激素在将代谢线索传达到生殖轴上的基本作用。