ERalpha and the metabolic syndrome

ERalpha 和代谢综合征

基本信息

  • 批准号:
    8186256
  • 负责人:
  • 金额:
    $ 38.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-15 至 2015-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Impaired ER1 action due to genetic inactivating mutations and reductions in ER1 levels in the context of obesity and menopause are associated with features of the metabolic syndrome (MS). We have recently recapitulated aspects of this syndrome in whole body ER1-/- mice. Clinical observations and findings from rodent studies conducted in our laboratory support the hypothesis that reduced ER1 expression may in part underlie the dramatic rise in the MS in women and potentially explain the lack of anticipated health benefit of postmenopausal estrogen replacement. To date, little is known regarding the mechanisms causing reduced ER1 levels in obese subjects or the specific tissue(s) conferring ER1-mediated effects on insulin sensitivity. Our research efforts are focused on defining the role of ER1 in skeletal muscle, given that muscle is a primary tissue contributing to whole body oxidative metabolism and insulin-mediated glucose disposal. In Aim1, we propose the use of mouse genetics, in combination with in vivo and in vitro approaches to generate muscle-specific ER1 loss- and gain-of-function mutations to test whether skeletal muscle ER1 is an important regulator of insulin sensitivity and adiposity. We provide compelling data showing that muscle ER1 maintains insulin action and protects against obesity, due in large part to its role in promoting oxidative metabolism and preventing tissue inflammation. Herein, we identify a novel role for ER1 in the regulation of mitochondrial morphology and turnover, as mitochondria are enlarged and misaligned, and mitophagy and biogenesis-related factors (e.g. the PINK1/Parkin pathway and Pgc11) are dysregulated in mice with muscle- specific ER1 deletion. In Aim 2, we will examine the role of ER1 in adaptations to endurance exercise. This aim is of particular clinical interest especially if the full health benefit of exercise cannot be achieved in muscle deficient in ER1. Indeed our findings show accelerated muscle fatigue and impaired exercise-mediated induction of factors controlling mitochondrial turnover in muscle-specific ER1 knockout mice. In Aim 3, we will test the hypothesis that reduced ER1 levels, as we observe in aged human muscle, results from protein hyperacetylation and targeted proteasomal degradation. Using newly generated tagged ER1 mutants that mimic or are resistant to acetylation coupled with an ERE-luciferase reporter system, we will investigate the relationship between acetylation state, transcriptional cofactor expression, and ER1 abundance. We now provide evidence that SIRT1, a class III HDAC with protein deacetylase function, is a central regulator of the "acetylation-phosphorylation switch" that appears to control ER1 levels and action in muscle. We anticipate that our findings will exert an important and lasting impact on the field of research and provide the critical foundation for the advancement of therapeutic strategies to treat metabolic dysfunction that underlies many female-related chronic diseases. PUBLIC HEALTH RELEVANCE: The incidence of the metabolic syndrome is rising dramatically in women and is associated with elevated morbidity and mortality secondary to type 2 diabetes, cardiovascular disease, hepatic dysfunction, and certain types of cancer. Human inactivating mutations in the estrogen receptor (ER) alpha are associated with features of the metabolic syndrome including insulin resistance and obesity, and we find that skeletal muscle-specific ERalpha knockout mice recapitulate a similar phenotype. Thus, we propose that strategies to maintain expression of ERalpha in glucoregulatory tissues, particularly skeletal muscle, may help prevent or ameliorate chronic disease in women.
描述(由申请人提供):由于遗传失活突变导致的ER 1作用受损以及肥胖和绝经背景下ER 1水平降低与代谢综合征(MS)的特征相关。我们最近在全身ER 1-/-小鼠中概括了这种综合征的各个方面。我们实验室进行的啮齿动物研究的临床观察和发现支持这一假设,即ER 1表达减少可能部分导致女性MS急剧上升,并可能解释绝经后雌激素替代缺乏预期的健康益处。迄今为止,关于肥胖受试者中引起ER 1水平降低的机制或赋予ER 1介导的对胰岛素敏感性的作用的特定组织知之甚少。我们的研究工作集中在确定ER 1在骨骼肌中的作用,因为肌肉是促进全身氧化代谢和胰岛素介导的葡萄糖处置的主要组织。 在Aim 1中,我们提出使用小鼠遗传学,结合体内和体外方法来产生肌肉特异性ER 1功能丧失和获得突变,以测试骨骼肌ER 1是否是胰岛素敏感性和肥胖的重要调节因子。我们提供了令人信服的数据,表明肌肉ER 1保持胰岛素作用并防止肥胖,这在很大程度上是由于其在促进氧化代谢和预防组织炎症中的作用。在本文中,我们确定了ER 1在线粒体形态和周转调节中的新作用,因为线粒体扩大和错位,并且在肌肉特异性ER 1缺失的小鼠中线粒体自噬和生物发生相关因子(例如PINK 1/Parkin途径和Pgc 11)失调。在目标2中,我们将研究ER 1在适应耐力运动中的作用。这一目标具有特别的临床意义,特别是如果运动的全部健康益处不能在ER 1缺陷的肌肉中实现。事实上,我们的研究结果表明,在肌肉特异性ER 1基因敲除小鼠中,肌肉疲劳加速,运动介导的控制线粒体周转的因子诱导受损。在目标3中,我们将检验这一假设,即我们在老年人肌肉中观察到的ER 1水平降低是由蛋白质过度乙酰化和靶向蛋白酶体降解引起的。使用新产生的标记ER 1突变体,模拟或耐乙酰化加上一个ERE-荧光素酶报告系统,我们将研究乙酰化状态,转录辅因子表达,和ER 1丰度之间的关系。我们现在提供的证据表明,SIRT 1,一种具有蛋白脱乙酰酶功能的III类HDAC,是“乙酰化-磷酸化开关”的中心调节因子,该开关似乎控制ER 1水平和肌肉中的作用。 我们预计,我们的研究结果将对研究领域产生重要而持久的影响,并为治疗代谢功能障碍的治疗策略的进步提供关键基础,代谢功能障碍是许多女性相关慢性疾病的基础。 公共卫生相关性:代谢综合征的发病率在女性中急剧上升,并且与继发于2型糖尿病、心血管疾病、肝功能障碍和某些类型的癌症的发病率和死亡率升高相关。人类雌激素受体(ER)α的失活突变与代谢综合征的特征相关,包括胰岛素抵抗和肥胖,我们发现骨骼肌特异性ER α敲除小鼠重现了类似的表型。因此,我们建议维持ER α在糖调节组织,特别是骨骼肌中表达的策略,可能有助于预防或改善女性慢性疾病。

项目成果

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Andrea L Hevener其他文献

Andrea L Hevener的其他文献

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{{ truncateString('Andrea L Hevener', 18)}}的其他基金

The impact of ERalpha on mitochondrial function in macrophages
ERα对巨噬细胞线粒体功能的影响
  • 批准号:
    10366022
  • 财政年份:
    2021
  • 资助金额:
    $ 38.5万
  • 项目类别:
The impact of ERalpha on mitochondrial function in macrophages
ERα对巨噬细胞线粒体功能的影响
  • 批准号:
    10597663
  • 财政年份:
    2021
  • 资助金额:
    $ 38.5万
  • 项目类别:
Systems-based approaches for investigating tissue communication during exercise
用于研究运动期间组织通讯的基于系统的方法
  • 批准号:
    10264084
  • 财政年份:
    2020
  • 资助金额:
    $ 38.5万
  • 项目类别:
Systems-based approaches for investigating tissue communication during exercise
用于研究运动期间组织通讯的基于系统的方法
  • 批准号:
    10438852
  • 财政年份:
    2020
  • 资助金额:
    $ 38.5万
  • 项目类别:
The impact of estrogen receptor alpha on cardiomyocellular metabolism and health
雌激素受体α对心肌细胞代谢和健康的影响
  • 批准号:
    10713760
  • 财政年份:
    2018
  • 资助金额:
    $ 38.5万
  • 项目类别:
ERalpha and the metabolic syndrome
ERalpha 和代谢综合征
  • 批准号:
    8690033
  • 财政年份:
    2011
  • 资助金额:
    $ 38.5万
  • 项目类别:
ERalpha and the metabolic syndrome
ERalpha 和代谢综合征
  • 批准号:
    8502475
  • 财政年份:
    2011
  • 资助金额:
    $ 38.5万
  • 项目类别:
ERalpha and the metabolic syndrome
ERalpha 和代谢综合征
  • 批准号:
    8320239
  • 财政年份:
    2011
  • 资助金额:
    $ 38.5万
  • 项目类别:
The Impact of Heat Shock Protein Expression on Inflammation and Insulin Action
热激蛋白表达对炎症和胰岛素作用的影响
  • 批准号:
    7837687
  • 财政年份:
    2009
  • 资助金额:
    $ 38.5万
  • 项目类别:
The Impact of Heat Shock Protein Expression on Inflammation and Insulin Action
热激蛋白表达对炎症和胰岛素作用的影响
  • 批准号:
    7850145
  • 财政年份:
    2009
  • 资助金额:
    $ 38.5万
  • 项目类别:

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