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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

基本信息

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
项目类别：
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

项目摘要

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.

涉及能量稳态的神经元回路正在被广泛探索；然而，内在的这些神经元调节的潜在机制刚刚开始被阐明，并且将是至关重要的用于了解与能量稳态相关的疾病（即肥胖、厌食、恶病质等）。这些神经元回路由许多不同的外周激素调节，包括 17β-雌二醇 (E2)。 E2，其中月经周期中的变化，是厌食症，导致食物摄入量和体重减少。 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) 发挥体内平衡功能改变控制神经元兴奋性的阳离子通道的表达和活性。因此，一个过去十年中神经内分泌学的新兴和重要领域一直是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。一种新型转基因小鼠品系 (ERα Ki/Ko) 在 ERα 上缺乏功能性 DNA 结合域蛋白，因此不表现出雌激素反应元件介导的转录。与这些小鼠一起使用野生型和全ERα KO，我们可以确定ERE依赖性和ERE非依赖性的作用能量稳态的转录和细胞信号传导。此外，越来越多的证据表明，两者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目标在改变正常生殖能力（包括其他下丘脑功能）之外的下丘脑受内源性雌激素控制。该应用概述的实验将检查多种受体介导的 E2（和环境雌激素）影响能量稳态和其他的途径下丘脑的功能在下丘脑。在第一个目标（K99/R00 的具体目标 3）中，我们将阐明 ERE 依赖性和 ERE 独立 E2 信号传导（ERα 和/或 Gq-mER）在能量控制中的作用体内平衡和下丘脑基因表达以及母亲暴露于环境雌激素的功能通过类似的机制。第二个目标（K99/R00 的特定目标 4）将检查电生理学环境雌激素暴露对 POMC 和 NPY 神经元活动和阳离子通道的影响体内和切片制剂中的表达。环境雌激素的电生理效应以前尚未研究过对下丘脑神经元活动的影响。由于最近的证据表明存在联系在发育时期接触 BPA 和成人肥胖之间，本研究的目标将解决基本问题这些化合物的神经学影响，并进一步增强我们对环境影响的了解使用新方法（转基因小鼠模型和电生理学）研究雌激素对人类健康的影响技术）并与整体动物研究相结合。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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