ERalpha and the metabolic syndrome

ERalpha 和代谢综合征

• 批准号: 8502475
• 负责人: Andrea L Hevener
• 金额: $ 32.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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/8502475
• 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

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）：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作用受损与代谢综合征（MS）的特征相关。我们最近在全身ER1-/-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结果支持这样的假设，即ER1表达减少可能在一定程度上导致女性MS的急剧上升，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，对于导致肥胖受试者ER1水平降低的机制或ER1介导胰岛素敏感性的特定组织知之甚少。鉴于肌肉是参与全身氧化代谢和胰岛素介导的葡萄糖处理的主要组织，我们的研究重点是确定ER1在骨骼肌中的作用。在Aim1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ER1缺失和功能获得突变，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维持胰岛素的作用并防止肥胖，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中的作用。在此，我们发现ER1在线粒体形态和转换调控中的新作用，因为线粒体扩大和错位，线粒体自噬和生物发生相关因子（如PINK1/Parkin通路和Pgc11）在肌肉特异性ER1缺失的小鼠中失调。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，特别是在ER1肌肉缺乏的情况下，运动的全部健康益处无法实现。事实上，我们的研究结果表明，在肌肉特异性ER1敲除小鼠中，肌肉疲劳加速和运动介导的线粒体转换控制因子诱导受损。在Aim 3中，我们将检验ER1水平降低的假设，正如我们在衰老的人类肌肉中观察到的那样，是蛋白质超乙酰化和靶向蛋白酶体降解的结果。使用新生成的标记ER1突变体，模拟或抵抗乙酰化，结合ere -荧光素酶报告系统，我们将研究乙酰化状态、转录辅助因子表达和ER1丰度之间的关系。我们现在提供的证据表明SIRT1是一种具有蛋白质去乙酰化酶功能的III类HDAC，是“乙酰化-磷酸化开关”的中心调节器，似乎控制ER1水平和肌肉中的作用。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。