Cross-talk between Estrogen and Metabolic Hormone Signaling in Kisspeptin Neurons

Kisspeptin 神经元中雌激素和代谢激素信号传导之间的串扰

基本信息

批准号：
10473890
负责人：
Martin Jeffrey Kelly
金额：
$ 49.14万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473890
关键词：
Address Adult Agonist Animals Appetite Stimulants Attenuated Biophysics Brown Fat Cations Clustered Regularly Interspaced Short Palindromic Repeats Coupled Cues Development Down-Regulation Dynorphins Eating Electrophysiology (science)Energy Metabolism Estradiol Estrogen Receptors Estrogens Female Fertility Frequencies Glutamate Receptor Glutamates Goals Gonadal Steroid Hormones Health Homeostasis Hormonal Hypothalamic structure Insulin KISS1 gene Lead Leptin Link Maintenance Measures Medial Dorsal Nucleus Mediating Membrane Messenger RNA Metabolic Metabolic hormone Metabolic syndrome Metabotropic Glutamate Receptors Molecular Molecular Biology Molecular Genetics Neurokinin B Neurons Neuropeptides Neurotransmitters Obesity Peptides Physiology Pro-Opiomelanocortin Property Regulation Reproduction Research Role Sex Differences Signal Pathway Signal Transduction Structure of dorsomedial hypothalamic nucleus Structure of nucleus infundibularis hypothalami Synapses Synaptic Transmission Temperature Whole-Cell Recordings estrogenic hormonal signals interdisciplinary approach knock-down mRNA Expression male neuronal circuitry neuronal excitability neuropeptide Y neurophysiology novel therapeutics optogenetics paraventricular nucleus parvocellular presynaptic programs receptor reduced food intake reproductive success tool transmission process vesicular glutamate transporter 2

项目摘要

Project Summary The long range goals of our research program has been to elucidate the mechanism(s) by which metabolic states and 17β-estradiol (E2) regulate arcuate nucleus kisspeptin (Kiss1ARH) neuronal circuits that are critical for coordinating energy homeostasis and reproduction in females. It is well known that E2 is anorexigenic, and that Kiss1 neurons, which are directly regulated by E2, are essential for pubertal development and adult reproductive success. However, their role in the control of other homeostatic functions is just emerging. Earlier, we found that Kiss1ARH neurons are excited by leptin and insulin via canonical transient receptor potential (TRPC) 5 channel signaling and proposed that they may serve as an important hub in the control of energy homeostasis. Recently, we found that high frequency optogenetic stimulation of Kiss1ARH neurons releases glutamate to excite the anorexigenic proopiomelanocortin (POMC) neurons but inhibit the orexigenic neuropeptide Y/agouti-related peptide (AgRP) neurons in both females and males. E2 increases vesicular glutamate transporter 2 (Vglut2) mRNA expression and glutamate release from female Kiss1ARH neurons to augment the POMC excitation and AgRP inhibition. In contrast, Vglut2 mRNA expression and glutamate release are increased in castrates as compared to intact males, illustrating an important sex difference in the synthesis and release of glutamate. Key excitatory cationic channels are upregulated by E2 leading to increased excitability and glutamatergic synaptic transmission. Recently, we have found that the selective membrane estrogen receptor (GqmER) agonist STX increases the excitability of Kiss1ARH neurons without downregulating the peptide expression. It also decreases food-intake in both females and males. Therefore, we hypothesize that estrogenic signaling in Kiss1ARH neurons is important for increasing Kiss1ARH neuronal excitability and maintenance of homeostatic functions critical for reproductive success. Our multidisciplinary approach incorporates a powerful set of cellular, molecular, genetic and optogenetic tools, and our combined expertise in molecular biology, electrophysiology, and whole animal physiology to address the following aims: (1) to measure the estrogenic-mediated increase in excitability of Kiss1ARH neurons using GCaMP6 and Voltron recordings; (2) to elucidate the estrogenic modulation of the synaptic input from Kiss1ARH to hypothalamic paraventricular nucleus neurons using optogenetic stimulation and its effects on food intake in E2 (STX)-treated females and STX-treated males; and (3) to elucidate the estrogenic modulation of synaptic input from Kiss1ARH neurons to hypothalamic dorsomedial nucleus neurons and its effects on energy expenditure in E2 (STX)-treated females and STX-treated males. Elucidating the circuits and signaling cascades underlying the actions of E2 and STX will provide a neurophysiological/neuropharmacological framework for a more thorough understanding of the cellular mechanisms by which Kiss1ARH neurons coordinate homeostatic functions with reproduction.

项目摘要我们研究计划的远程目标是阐明代谢状态的机制和17β-雌二醇（E2）调节弧形核心肽（Kiss1arh）神经元回路，这对于至关重要在女性中协调能量稳态和繁殖。由E2直接定制的KISS1神经元对于青春期开发和成年人至关重要但是，我们的其他稳态功能是正确的。通过典型瞬态受体电势（TRPC）5通道激发了KISS1ARH神经元激发瘦素和胰岛素激发信号传导和支撑物是，是作为控制能量稳态的重要枢纽。我们。厌食症的肌蛋白酶素（POMC）神经元，但抑制了甲状腺素神经肽Y/Agouti相关女性和男性中的肽（AGRP）神经元增加了水泡谷氨酸转运蛋白2（VGLUT2） mRNA Express和谷氨酸从雌性Kiss1arons释放到POMC激发，并且 AGRP侵袭。与完整的男性相比，说明了谷氨酸的合成和释放的重要性别差异。兴奋性阳离子通道被E2上升，导致令人兴奋的兴奋性和谷氨酸突触增加传播。用果皮表达的神经元增加了Kiss1arh神经元的兴奋性。因此，女性和男性的食物。对于增加Kiss1arh神经兴奋性兴奋性和对体内统治的维持态度至关重要生殖成功。我们的多学科方法结合了一组强大的细胞和光遗传学工具，以及我们在分子生物学，电生理学和全动物方面的综合专业知识解决以下目的的生理学：（1）测量雌激素介导的兴奋性增加的增加使用GCAMP6和Voltron录音的Kiss1arh神经元；使用光遗传刺激和它对经E2（STX）治疗的女性和STX治疗的雄性的影响；调节从Kiss1aron到下丘脑背核神经元及其ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ETS ET E2（STX）的女性和STX - 育男性中的Onergy支出。 E2和STX的作用的基础级联将提供神经生理/神经药理学框架，以更透彻地理解亲吻1arhnurons坐标的细胞机制稳态功能具有繁殖。