Estrogen Regulation of Channels Involved in the Control of Energy Homeostatis

雌激素对参与能量稳态控制的通道的调节

• 批准号: 8678586
• 负责人: Troy Adam Roepke
• 金额: $ 21.49万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8678586
• 关键词: Address; Adult; Affect; Animals; Anorexia; Appetite Depressants; Applications Grants; Award; Back; Body Weight; Breeding; Cachexia; Cations; Cell physiology; Circadian Rhythms; Coupled; DNA Binding Domain; Darkness; Data; Data Collection; Databases; Development; Disease; Eating; Environmental Estrogen; Estradiol; Estrogen Receptors; Estrogens; Event; Exhibits; Exposure to; Extramural Activities; Feeding behaviors; Female; Funding; GTP-Binding Proteins; Gene Expression; Genetic Transcription; Goals; Health; Heating; Homeostasis; Hormones; Human; Hurricane; Hypothalamic structure; Knowledge; Link; Maternal Exposure; Mediating; Membrane; Menstrual cycle; Metabolic syndrome; Mouse Strains; Mus; NIH Program Announcements; Neuroendocrinology; Neurologic; Neurons; New Jersey; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Pathway interactions; Peripheral; Phase; Physiological; Phytoestrogens; Preparation; Progress Reports; Proteins; Regulation; Research; Response Elements; Role; Secure; Services; Signal Transduction; Slice; Steroids; Techniques; Temperature; Time; Transgenic Mice; Transgenic Organisms; Universities; Weight Gain; Zearalenone; animal care; animal colony; base; bisphenol A; energy balance; environmental chemical exposure; experience; falls; in vivo; male; mouse model; neuronal excitability; nonylphenol; novel; novel strategies; reproductive; research study; response; young adult

The neuronal circuits involved in energy homeostasis are being extensively explored; however, the intrinsic mechanisms underlying the regulation of these neurons are just beginning to be elucidated and will be critical for understanding disorders associated with energy homeostasis (i.e., obesity, anorexia, cachexia, etc.). These neuronal circuits are modulated by many different peripheral hormones including 17β-estradiol (E2). E2, which varies during the menstrual cycle, is anorectic leading to decreased food intake and body weight. E2 can alter homeostatic functions by activating ERα and novel G-protein coupled membrane estrogen receptors (GqmER) to alter the expression and activity of cation channels that control neuronal excitability. Hence, an emerging and significant field in neuroendocrinology within the past decade has been the convergence of membrane-initiated steroid signaling and physiological effects. The membrane-initiated events utilized by E2 involve activation of a host of known pathways that control neuronal excitability, gene expression and cellular functions. A novel transgenic strain of mice (ERα Ki/Ko) lack a functional DNA binding domain on the ERα protein and, thus exhibit no Estrogen Response Element-mediated transcription. Using these mice along with wild type and full ERα KO, we can determine the actions of ERE-dependent and ERE-independent transcription and cell signaling on energy homeostasis. Furthermore, there is growing evidence that both of these types of signaling events are potential targets for environmental estrogens (bisphenol A (BPA), alkylphenols, phytoestrogens, etc.). Therefore, environmental estrogens have a multiplicity of potential targets in the hypothalamus outside of altering normal reproductive capacity including other hypothalamic functions controlled by endogenous estrogen. Experiments outlined this application will examine the multiple receptormediated pathways that E2 (and environmental estrogens) impact energy homoeostasis and other hypothalamic functions in the hypothalamus. In the first aim, Specific Aim 3 of K99/R00, we will elucidate the effects of ERE-dependent and ERE-independent E2 signaling (ERα and/or Gq-mER) in the control of energy homeostasis and hypothalamic gene expression and if maternal exposure to environmental estrogens function through similar mechanisms. The second aim, Specific Aim 4 of K99/R00) will examine the electrophysiological effects of exposures to environmental estrogens on POMC and NPY neuronal activity and cation channel expression both in vivo and in slice preparations. The electrophysiological effects of environmental estrogens on hypothalamic neuronal activity has not been examine previously. Since recent evidence suggests a link between developmental exposure to BPA and adult obesity, the goals of this research will address basic neurological effects of these compounds and further enhance our knowledge of the impacts environmental estrogens have on human health using novel approaches (transgenic mouse models and electrophysiological techniques) and integration with whole animal studies.

参与能量稳态的神经元回路正在被广泛探索;然而， 这些神经元的调节机制才刚刚开始阐明，将是至关重要的 为了理解与能量稳态相关的疾病（即，肥胖、厌食、恶病质等）。这些 神经元回路由包括17β-雌二醇（E2）在内的许多不同的外周激素调节。E2的 在月经周期中变化，是厌食导致减少食物摄入量和体重。E2可以改变 通过激活ERα和新型G蛋白偶联膜雌激素受体（GqmER）发挥稳态功能 以改变控制神经元兴奋性的阳离子通道的表达和活性。所以安 在过去的十年中，神经内分泌学的一个新兴的重要领域是以下方面的融合： 膜引发的类固醇信号传导和生理效应。E2利用的膜启动事件 涉及激活许多控制神经元兴奋性、基因表达和细胞的已知途径 功能协调发展的一种新的转基因小鼠（ERα Ki/Ko）缺乏ERα上的功能性DNA结合结构域 蛋白质，因此不显示雌激素应答元件介导的转录。利用这些老鼠沿着 野生型和完全ERα KO，我们可以确定ER依赖性和ER非依赖性的作用 转录和细胞信号对能量稳态的影响。越来越多的证据表明， 这些类型的信号事件是环境雌激素（双酚A（BPA）， 烷基酚、植物雌激素等）。因此，环境雌激素具有多种潜在靶点 除了改变正常的生殖能力，包括其他下丘脑功能外， 由内源性雌激素控制。本申请概述的实验将检查多个受体介导的 E2（和环境雌激素）影响能量稳态和其他 下丘脑的功能。在K99/R 00的第一个目标，具体目标3中，我们将阐明 ER依赖性和ER非依赖性E2信号传导（ERα和/或Gq-mER）在能量控制中的作用 稳态和下丘脑基因表达以及母体是否暴露于环境雌激素功能 通过类似的机制。第二个目标，K99/R 00的特定目标4）将检查电生理学 环境雌激素暴露对POMC和NPY神经元活性及阳离子通道的影响 在体内和切片制备中表达。环境雌激素的电生理效应 对下丘脑神经元活动的影响以前没有研究过。因为最近的证据表明 在发育期暴露于BPA和成人肥胖之间，这项研究的目标将解决基本的 这些化合物对神经系统的影响，并进一步增强我们对环境影响的了解 雌激素对人类健康的影响（转基因小鼠模型和电生理学） 技术）和与整体动物研究的整合。

项目成果

Regulation of gene expression by 17β-estradiol in the arcuate nucleus of the mouse through ERE-dependent and ERE-independent mechanisms.

• DOI: 10.1016/j.steroids.2016.01.003
• 发表时间: 2016-03
• 期刊: Steroids
• 影响因子: 2.7
• 作者: Yang JA;Mamounis KJ;Yasrebi A;Roepke TA
• 通讯作者: Roepke TA

The loss of ERE-dependent ERα signaling potentiates the effects of maternal high-fat diet on energy homeostasis in female offspring fed an obesogenic diet.

ERE 依赖性 ERα 信号的丧失增强了母亲高脂肪饮食对肥胖饮食喂养的雌性后代能量稳态的影响。

• DOI: 10.1017/s2040174419000515
• 发表时间: 2020
• 期刊: Journal of developmental origins of health and disease
• 影响因子: 1.7
• 作者: Roepke,TroyA;Yasrebi,Ali;Villalobos,Alejandra;Krumm,ElizabethA;Yang,JenniferA;Mamounis,KyleJ
• 通讯作者: Mamounis,KyleJ