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（由申请人提供）：由于遗传失活突变导致的 ER1 作用受损以及肥胖和更年期背景下 ER1 水平的降低与代谢综合征 (MS) 的特征相关。我们最近在全身 ER1-/- 小鼠中重现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结果支持了以下假设：ER1 表达减少可能在一定程度上是女性 MS 急剧上升的原因，并可能解释绝经后雌激素替代疗法缺乏预期的健康益处。迄今为止，关于导致肥胖受试者 ER1 水平降低的机制或赋予 ER1 介导的胰岛素敏感性影响的特定组织知之甚少。鉴于肌肉是促进全身氧化代谢和胰岛素介导的葡萄糖处理的主要组织，我们的研究工作重点是确定 ER1 在骨骼肌中的作用。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 ER1 功能丧失和功能获得突变，以测试骨骼肌 ER1 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 ER1 可以维持胰岛素作用并预防肥胖，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方面的作用。在此，我们确定了 ER1 在调节线粒体形态和周转中的新作用，因为在具有肌肉特异性的小鼠中，线粒体增大和错位，线粒体自噬和生物发生相关因子（例如 PINK1/Parkin 通路和 Pgc11）失调。 ER1 删除。在目标 2 中，我们将研究 ER1 在适应耐力运动中的作用。这一目标具有特殊的临床意义，特别是如果缺乏 ER1 的肌肉无法实现运动的全部健康益处。事实上，我们的研究结果表明，在肌肉特异性 ER1 敲除小鼠中，肌肉疲劳加速，运动介导的线粒体周转控制因子诱导受损。在目标 3 中，我们将检验这样的假设：正如我们在衰老的人类肌肉中观察到的那样，ER1 水平降低是由于蛋白质过度乙酰化和靶向蛋白酶体降解造成的。使用新生成的、模拟或抵抗乙酰化的标记 ER1 突变体以及 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 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”的中央调节器，似乎控制肌肉中的 ER1 水平和作用。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，并为治疗许多女性相关慢性疾病的代谢功能障碍的治疗策略的进步提供关键基础。