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 我们研究计划的长期目标一直是阐明代谢的机制(S) STATES和17β-雌二醇(E_2)调节关键的弓状核Kisspeptin(Kiss1ARH)神经元回路 用来协调雌性体内的能量平衡和生殖。众所周知，雌二醇是厌食性的，而且 由E2直接调节的Kiss1神经元对青春期发育和成人是必不可少的 繁衍成功。然而，它们在控制其他体内平衡功能方面的作用才刚刚显现。 早些时候，我们发现Kiss1ARH神经元通过典型的瞬变被瘦素和胰岛素去极化/兴奋 受体潜力(TRPC)5通道信号，并提出它们可能是一个重要的中枢。 控制能量动态平衡。最近，我们发现Kiss1ARH的高频光遗传刺激 神经元释放谷氨酸兴奋厌食性前阿片黑素皮质素(POMC)神经元，但抑制 食欲神经肽Y/刺鼠相关肽(AgRP)神经元。雌二醇增加囊泡谷氨酸 雌性Kiss1ARH神经元转运蛋白2基因的表达和谷氨酸的释放 POMC兴奋和AgRP抑制。此外，Kiss1ARH神经元投射并兴奋AVPV/PEN Kiss1神经元 通过谷氨酸，驱动促性腺激素释放激素和促黄体生成素激增。因此，Kiss1ARH神经元似乎整合了代谢 激素和性腺类固醇信号通过多种途径调节能量平衡和生殖 神经递质。关键的兴奋性阳离子通道被E2上调，导致兴奋性和 谷氨酸能突触传递，而肽的表达和传递被 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不下调Kiss1ARH神经元兴奋性 多肽的表达。因此，我们假设Kiss1ARH神经元中的雌激素信号是重要的 增加Kiss1ARH神经元的兴奋性和维持对生殖至关重要的稳态功能 成功。我们的多学科方法结合了一套强大的细胞、分子、遗传学和 光遗传工具，以及我们在分子生物学、电生理学和整个动物方面的综合专业知识 生理学以解决以下目标：(1)测量雌激素介导的兴奋性增加 用GCaMP6和Voltron记录Kiss1ARH神经元；(2)阐明 Kiss1ARH向下丘脑室旁核神经元的突触传入 以及对食物摄取的影响；以及(3)阐明Kiss1ARH对突触输入的雌激素调节作用 神经元到下丘脑背内侧核神经元及其对能量消耗的影响。澄清 E2和选择性GqmER激动剂STX的作用背后的电路和信号级联 神经生理学/神经药理学框架，以更彻底地了解细胞 Kiss1ARH神经元协调内稳态功能与生殖的机制。

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

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

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

Estrogen signaling in hypothalamic circuits controlling reproduction.

在控制繁殖的下丘脑回路中的雌激素信号传导。

• DOI: 10.1016/j.brainres.2010.08.082
• 发表时间: 2010-12-10
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Kelly MJ;Qiu J
• 通讯作者: Qiu J