The role of ERRalpha in mitochondrial function and insulin resistance

描述（申请人提供）：2型糖尿病是西方和发展中国家最常见的代谢性疾病，迅速成为世界性流行病。虽然2型糖尿病的确切主要原因尚未确定，但很明显，胰岛素抵抗，即胰岛素不能促进葡萄糖的处理，在疾病的发展中起着重要作用。线粒体氧化功能下降和随之增加的细胞内脂质积累被认为是胰岛素抵抗的潜在原因。值得注意的是，胰岛素抵抗或2型糖尿病患者的肌肉编码线粒体蛋白的基因表达降低，线粒体和线粒体酶含量降低，线粒体氧化磷酸化能力降低。最近的研究已经阐明了控制线粒体功能的特定转录网络。这些网络的扰动在多大程度上促进了胰岛素抵抗和糖尿病的发展目前尚不清楚。这项工作将验证孤儿核受体雌激素相关受体α (ERRa)是体内骨骼肌中调节线粒体氧化能力和胰岛素敏感性的关键转录因子的假设。为了支持这一假设，在肌肉中，ERRa被刺激线粒体生物发生和功能的信号和途径激活，在培养细胞中，ERRa调节线粒体生物发生和功能，缺乏ERRa的小鼠（ERRa KO）编码线粒体蛋白的基因表达减少。为了验证我们的假设，我们将1)比较野生型和ERRa KO小鼠肌肉中的线粒体生物发生和功能，以确定ERRa在骨骼肌线粒体功能中的作用；2)评估ERRa对野生型和ERRa KO小鼠以及具有或缺乏ERRa的原代肌细胞培养中胰岛素敏感性的影响。我们希望证明ERRa调节肌肉线粒体代谢，并在2型糖尿病之前的胰岛素抵抗的发展中发挥重要作用。这些研究将有助于开发旨在恢复线粒体功能、改善胰岛素抵抗和预防糖尿病相关病理的治疗策略。与公共卫生有关。糖尿病是世界范围内的一个主要健康问题，已达到流行病的程度。胰岛素抵抗在2型糖尿病的发展中起着重要作用，即最普遍的疾病形式。这项工作使用动物模型来确定转录调节因子ERRa控制线粒体功能和体内胰岛素敏感性的程度。建立线粒体功能下降和胰岛素抵抗易感性的动物模型将有助于评估改善胰岛素敏感性和降低糖尿病发病率的策略。

DESCRIPTION (provided by applicant): Type 2 diabetes is the most prevalent metabolic disorder in Western and developing countries, rapidly becoming a worldwide epidemic. Although the exact primary cause(s) of type 2 diabetes are not yet defined, it is clear that insulin resistance, i.e. the inability of insulin to promote glucose disposal, plays a major role in the development of the disease. Decreased mitochondrial oxidative function and an ensuing increased intracellular lipid accumulation have been proposed as underlying causes for insulin resistance. Notably, muscle in individuals with insulin resistance or type 2 diabetes has decreased expression of genes encoding mitochondrial proteins, lower content of mitochondria and mitochondrial enzymes, and reduced mitochondrial oxidative phosphorylation capacity. Recent studies have elucidated specific transcriptional networks that control mitochondrial function. The extent to which perturbations in these networks contribute to insulin resistance and the development of diabetes is currently not clear. The proposed work will test the hypothesis that the orphan nuclear receptor Estrogen Related Receptor alpha (ERRa) is a critical transcription factor regulating mitochondrial oxidative capacity and insulin sensitivity in skeletal muscle in vivo. In support of the hypothesis, ERRa is activated by signals and pathways that stimulate mitochondrial biogenesis and function in muscle, ERRa regulates mitochondrial biogenesis and function in cultured cells, and mice lacking ERRa (ERRa KO) have decreased expression of genes encoding mitochondrial proteins. To test our hypothesis we will 1) compare mitochondrial biogenesis and function in muscle of wild-type and ERRa KO mice to determine the role of ERRa in mitochondrial function in skeletal muscle; and 2) assess the effect of ERRa on insulin sensitivity in wild-type and ERRa KO mice, and in primary muscle cell cultures having or lacking ERRa. We expect to demonstrate that ERRa regulates muscle mitochondrial metabolism and plays an important role in the development of the insulin resistance that precedes type 2 diabetes. These studies will enable development of therapeutic strategies aiming at restoring mitochondrial function, ameliorating insulin resistance and preventing diabetes-associated pathologies. Relevance to public health. Diabetes is a major health problem worldwide, reaching epidemic proportions. Insulin resistance plays a major role in the development of type 2 diabetes, i.e. the most prevalent form of the disease. The proposed work uses animal models to determine the extent to which the transcriptional regulator ERRa controls mitochondrial function and determines insulin sensitivity in vivo. Establishment of an animal model with decreased mitochondrial function and susceptibility to insulin resistance will be useful for evaluating strategies that improve insulin sensitivity and decrease the incidence of diabetes.