Crosstalk 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: 10246663
• 负责人: Martin Jeffrey Kelly
• 金额: $ 26.18万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246663
• 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; GNRH1 gene; 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; 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; neuronal circuitry; neuronal excitability; neuropeptide Y; neurophysiology; novel therapeutics; optogenetics; paraventricular nucleus; parvocellular; 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 depolarized/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. E2 increases vesicular glutamate transporter 2 (Vglut2) mRNA expression and glutamate release from female Kiss1ARH neurons to augment the POMC excitation and AgRP inhibition. Also, Kiss1ARH neurons project to and excite AVPV/PeN Kiss1 neurons via glutamate, which drives the GnRH and LH surges. Thus, Kiss1ARH neurons appear to integrate metabolic hormone and gonadal steroid signaling to regulate both energy homeostasis and reproduction via multiple neurotransmitters. Key excitatory cationic channels are upregulated by E2 leading to increased excitability and glutamatergic synaptic transmission, whereas peptide expression and transmission are attenuated by the classical estrogen receptor (ER) signaling pathways. Recently, we have found that the selective membrane estrogen receptor (GqmER) agonist STX increases the excitability of Kiss1ARH neurons without downregulating the peptide expression. 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; and (3) to elucidate the estrogenic modulation of synaptic input from Kiss1ARH neurons to hypothalamic dorsomedial nucleus neurons and its effects on energy expenditure. Elucidating the circuits and signaling cascades underlying the actions of E2 and the selective GqmER agonist 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 我们的研究计划的长期目标是阐明代谢的机制， 状态和17β-雌二醇（E2）调节弓状核kisspeptin（Kiss 1ARH）神经元回路， 协调能量平衡和女性生殖的能力。众所周知，E2是致癌的， Kiss 1神经元直接受E2调节，对青春期发育和成年至关重要。 繁殖成功然而，它们在控制其他稳态功能中的作用才刚刚出现。 早期，我们发现Kiss 1ARH神经元被瘦素和胰岛素通过经典瞬变去极化/兴奋， 受体电位（TRPC）5通道信号，并提出他们可能作为一个重要的枢纽，在 能量平衡的控制最近，我们发现高频光遗传学刺激Kiss 1ARH， 神经元释放谷氨酸以兴奋促氧化的阿黑皮素原（POMC）神经元，但抑制 食欲神经肽Y/刺豚鼠相关肽（AgRP）神经元。E2增加囊泡谷氨酸 转运蛋白2（VAP 2）mRNA表达和谷氨酸释放从女性Kiss 1ARH神经元，以增加 POMC兴奋和AgRP抑制。此外，Kiss 1ARH神经元投射并兴奋AVPV/Pen Kiss 1神经元 通过谷氨酸盐，它驱动促性腺激素释放激素和促黄体激素激增。因此，Kiss 1ARH神经元似乎整合代谢 激素和性腺类固醇信号传导以通过多种途径调节能量稳态和生殖 神经传递素关键的兴奋性阳离子通道被E2上调，导致兴奋性增加， 肽的表达和传递被突触传递减弱， 经典的雌激素受体（ER）信号通路。最近，我们发现选择性膜 雌激素受体（GqmER）激动剂STX增加Kiss 1ARH神经元的兴奋性而不下调 肽的表达。因此，我们假设Kiss 1ARH神经元中的雌激素信号是重要的 用于增加Kiss 1ARH神经元兴奋性和维持生殖关键的稳态功能 成功我们的多学科方法结合了一套强大的细胞，分子，遗传和 光遗传学工具，以及我们在分子生物学，电生理学和整个动物 （1）测量雌激素介导的兴奋性增加， 用GCaMP 6和Voltron记录Kiss 1ARH神经元;（2）阐明雌激素对Kiss 1ARH神经元的调节作用， 利用光遗传学刺激从Kiss 1ARH到下丘脑室旁核神经元的突触输入 研究Kiss 1ARH对大鼠摄食的影响;（3）阐明Kiss 1ARH对突触输入的雌激素调节作用 神经元对下丘脑背内侧核神经元的作用及其对能量消耗的影响。阐明 E2和选择性GqmER激动剂STX的作用背后的电路和信号级联将提供 一个神经生理学/神经药理学框架，用于更全面地了解细胞 Kiss 1ARH神经元协调生殖稳态功能的机制。

项目成果

17Beta-estradiol regulation of T-type calcium channels in gonadotropin-releasing hormone neurons.

• DOI: 10.1523/jneurosci.2962-09.2009
• 发表时间: 2009-08-26
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Zhang C;Bosch MA;Rick EA;Kelly MJ;Rønnekleiv OK
• 通讯作者: Rønnekleiv OK

Receptor subtypes and signal transduction mechanisms contributing to the estrogenic attenuation of cannabinoid-induced changes in energy homeostasis.

• DOI: 10.1159/000338669
• 发表时间: 2013
• 期刊: Neuroendocrinology
• 影响因子: 4.1
• 作者: Washburn N;Borgquist A;Wang K;Jeffery GS;Kelly MJ;Wagner EJ
• 通讯作者: Wagner EJ

Fasting and 17β-estradiol differentially modulate the M-current in neuropeptide Y neurons.

• DOI: 10.1523/jneurosci.1395-11.2011
• 发表时间: 2011-08-17
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Roepke TA;Qiu J;Smith AW;Rønnekleiv OK;Kelly MJ
• 通讯作者: Kelly MJ

Kisspeptin activation of TRPC4 channels in female GnRH neurons requires PIP2 depletion and cSrc kinase activation.

Kisspeptin 激活女性 GnRH 神经元中的 TRPC4 通道需要 PIP2 耗竭和 cSrc 激酶激活。

• DOI: 10.1210/en.2013-1180
• 发表时间: 2013
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Zhang,Chunguang;Bosch,MarthaA;Rønnekleiv,OlineK;Kelly,MartinJ
• 通讯作者: Kelly,MartinJ

17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta.

• DOI: 10.1002/cne.21901
• 发表时间: 2009-01-20
• 期刊: JOURNAL OF COMPARATIVE NEUROLOGY
• 影响因子: 2.5
• 作者: Bosch, Martha A.;Hou, Jingwen;Fang, Yuan;Kelly, Niartin J.;Ronnekleiv, Oline K.
• 通讯作者: Ronnekleiv, Oline K.