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):在肥胖和更年期的背景下,由于基因失活突变和ER1水平降低而导致的ER1活性受损与代谢综合征(MS)的特征有关。我们最近在ER1-/-小鼠身上总结了这种综合征的一些方面。临床观察和在我们实验室进行的啮齿动物研究结果支持这一假说,即ER1表达减少可能是女性多发性硬化症显著增加的部分原因,并可能解释绝经后雌激素替代治疗缺乏预期的健康益处。到目前为止,关于肥胖受试者中ER1水平降低的机制或赋予ER1介导的胰岛素敏感性效应的特定组织(S),人们知之甚少。我们的研究重点是确定ER1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Aim1中,我们建议使用小鼠遗传学,结合体内和体外的方法来产生肌肉特异性的ER1功能丧失和获得突变,以测试骨骼肌ER1是否是胰岛素敏感性和肥胖症的重要调节因子。我们提供了令人信服的数据,表明肌肉ER1维持胰岛素作用并预防肥胖,这在很大程度上是由于它在促进氧化代谢和预防组织炎症方面的作用。在这里,我们确定了ER1在线粒体形态和周转调节中的新角色,因为在肌肉特异性ER1缺失的小鼠中,线粒体变大和错位,有丝分裂和生物发生相关的因子(如PINK1/Parkin通路和Pgc11)调节失调。在目标2中,我们将研究ER1在耐力运动适应中的作用。这一目的具有特别的临床意义,特别是如果运动对缺乏ER1的肌肉不能完全实现健康益处的话。事实上,我们的发现表明,在肌肉特异的ER1基因敲除小鼠中,肌肉疲劳加速和运动介导的控制线粒体周转的因素的诱导受到损害。在目标3中,我们将验证一种假设,即ER1水平降低,正如我们在老年人肌肉中观察到的那样,是蛋白质超乙酰化和靶向性蛋白酶体降解的结果。使用新产生的模拟或抵抗乙酰化的标记ER1突变体与ERE-荧光素酶报告系统相结合,我们将研究乙酰化状态、转录辅因子表达和ER1丰度之间的关系。我们现在提供的证据表明,SIRT1,一种具有蛋白质脱乙酰酶功能的III类HDAC,是“乙酰化-磷酸化开关”的中央调节因子,似乎控制着肌肉中ER1的水平和作用。我们预计,我们的发现将对研究领域产生重要和持久的影响,并为推进治疗代谢功能障碍的治疗策略提供关键基础,代谢功能障碍是许多女性相关慢性病的基础。 公共卫生相关性:代谢综合征在女性中的发病率急剧上升,并与继发于2型糖尿病、心血管疾病、肝功能障碍和某些类型癌症的发病率和死亡率上升有关。人类雌激素受体(ER)α的失活突变与包括胰岛素抵抗和肥胖在内的代谢综合征的特征有关,我们发现骨骼肌特异的ERα基因敲除小鼠具有类似的表型。因此,我们建议,在糖调节组织,特别是骨骼肌中保持ERa表达的策略,可能有助于预防或改善女性的慢性病。

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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