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

• 批准号: 10295726
• 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
• 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/10295726
• 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

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）神经元电路，这对于至关重要 协调女性的能量稳态和繁殖。众所周知，E2是厌食症，并且 由E2直接调节的KISS1神经元对于青春期开发和成人生殖至关重要 成功。但是，它们在控制其他稳态功能中的作用只是出现。早些时候，我们发现 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 信号传导并提出它们可以作为控制能量稳态的重要枢纽。最近， 我们发现，亲吻神经元的高频光遗传刺激会释放谷氨酸，以激发谷氨酸 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 女性和雄性的肽（AGRP）神经元。 E2增加囊泡谷氨酸转运蛋白2（VGLUT2） mRNA表达和谷氨酸从雌性Kiss1arh神经元释放，以增强POMC兴奋和 AGRP抑制。相比 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。钥匙 E2更新了兴奋性阳离子通道，从而增加了兴奋性和谷氨酸能突触 传播。最近，我们发现选择性膜雌激素受体（GQMER）激动剂STX 在不下调胡椒表达的情况下，增加了Kiss1arh神经元的兴奋。它也减少 女性和雄性的食物感。因此，我们假设Kiss1arh神经元中的雌激素信号传导 对于增加Kiss1Arh神经元的激动和维持体内稳态功能至关重要的重要性很重要 生殖成功。我们的多学科方法结合了一组强大的细胞，分子，遗传 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的增加 使用GCAMP6和Voltron录音的Kiss1arh神经元； （2）阐明 使用光遗传刺激和 它对经E2（STX）治疗的女性和STX治疗的雄性中食物摄入的影响； （3）阐明雌激素 从KISS1ARH神经元到下丘脑背侧核神经元及其作用的突触输入调节 关于E2（STX）治疗的女性和STX治疗的男性的能量消耗。阐明电路和信号 E2和STX的作用的基础级联将提供神经生理/神经药物 框架以更透彻地理解亲吻神经元坐标的细胞机制 稳态功能具有繁殖。