ERalpha and the metabolic syndrome

ERalpha 和代谢综合征

基本信息

批准号：
8320239
负责人：
Andrea L Hevener
金额：
$ 33.5万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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

来源：
https://reporter.nih.gov/project-details/8320239
关键词：
Acetylation Adipose tissue Agonist Biogenesis Cardiovascular Diseases Cell Respiration Cell physiology Chronic Disease Clinical Consumption Coupled Data Deacetylase Diet Estrogen Receptor alpha Estrogen Receptors Estrogen Replacements Exercise Fatigue Fatty Acids Fatty acid glycerol esters Female Foundations Functional disorder Genetic Health Benefit Hepatic Histone Deacetylase Human In Vitro Incidence Inflammation Insulin Insulin Resistance Intervention Knock-out Knockout Mice Laboratories Ligands Lipids Liver Luciferases Lysine Maintenance Mediating Menopause Metabolic Metabolic syndrome Metabolism Mitochondria Morbidity - disease rate Morphology Mus Muscle Muscle Cells Muscle Fatigue Mutation Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity PINK1 gene Pathway interactions Phenotype Phosphorylation Physical activity Plasmids Post-Translational Protein Processing Postmenopause Protein Isoforms Proteins Receptor Activation Refractory Regulation Reporter Research Resistance Rodent Role Secondary to Signal Transduction Skeletal Muscle Steroid Receptors Syndrome System Testing Therapeutic Tissues Training VP 16 Woman aged cancer type cofactor diabetes risk fatty acid metabolism fatty acid oxidation gain of function gain of function mutation glucose disposal improved in vivo insulin sensitivity interest lentiviral-mediated loss of function mortality multicatalytic endopeptidase complex muscle metabolism mutant novel obesity treatment overexpression parkin gene/protein prevent promoter receptor expression recombinase response restoration small hairpin RNA

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.

描述（申请人提供）：由于肥胖和更年期的遗传失活突变和ER1水平降低而导致的ER1作用受损与代谢综合征（MS）的特征有关。我们最近在全身ER1 - / - 小鼠中概括了该综合征的方面。在我们的实验室中进行的啮齿动物研究的临床观察结果和发现支持以下假设：降低ER1表达可能部分是女性MS的急剧上升，并有可能解释了绝经后雌激素替代的预期健康益处。迄今为止，关于导致肥胖受试者的ER1水平降低的机制或赋予ER1介导对胰岛素敏感性作用的特定组织的机制知之甚少。我们的研究工作重点是定义ER1在骨骼肌中的作用，因为肌肉是有助于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，结合体内和体外方法来产生肌肉特异性的ER1损失和功能增益突变，以测试骨骼肌ER1是否是胰岛素敏感性和肥胖性的重要调节剂。我们提供了令人信服的数据，表明肌肉ER1保持胰岛素作用并预防肥胖症，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。本文中，我们确定了ER1在线粒体形态和周转调节中的新作用，因为线粒体被扩大且未对齐，并且线粒体和生物发生相关因素（例如，在肌肉 - 特定ER1 deletion的小鼠中，pink1/parkin途径和PGC11的PINK1/PARKIN途径和PGC11）失调。在AIM 2中，我们将研究ER1在适应耐力运动中的作用。该目标特别具有临床意义，尤其是如果在ER1缺乏肌肉中无法实现运动的全部健康益处。确实，我们的发现表明，肌肉疲劳加速，运动介导的诱导诱导了控制肌肉特异性ER1敲除小鼠线粒体周转的因素。在AIM 3中，我们将检验以下假设：正如我们在年龄的人类肌肉中所观察到的那样，蛋白质高乙酰化和靶向蛋白酶体降解所致。使用新生成的标记的ER1突变体，该突变体模仿或对乙酰化具有与ERE-luciferase Reporter System相结合的乙酰化，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。我们现在提供证据表明，SIRT1是具有蛋白质脱乙酰基酶功能的III类HDAC，是“乙酰化磷酸化开关”的中心调节剂，它似乎控制着肌肉中的ER1水平和作用。我们预计我们的发现将对研究领域产生重要而持久的影响，并为治疗许多与女性相关的慢性疾病的基础的治疗策略的发展奠定了关键的基础。