Mitochondrial regulators and insulin signaling

描述（由申请人提供）：线粒体功能障碍和胰岛素抵抗之间的潜在联系一直很有兴趣。在我们鉴定线粒体生物发生和功能的新调节因子的研究中，我们发现Wnt在培养肌肉细胞中的激活可诱导线粒体增殖并增强胰岛素敏感性，部分原因是通过诱导受体蛋白胰岛素受体底物-1 （IRS-1）。虽然Wnt信号网络的研究主要是在细胞增殖、分化和发育过程中进行的，但现在越来越多的证据表明Wnt信号通路与代谢有关。特别是，Wnt通路基因的等位基因变异与2型糖尿病易感性之间有很强的关联。我们现在试图评估Wnt信号功能缺失在肌肉细胞中产生胰岛素抵抗的可能性。在Aim 1中，我们将使用Wnt拮抗剂来评估抑制Wnt信号传导对线粒体生理和肌肉胰岛素敏感性的影响，同时使用细胞培养和动物模型。在Aim 2中，我们将在线粒体生理学和肌肉胰岛素敏感性的背景下研究非规范和规范Wnt信号通路之间的功能相互作用。细胞培养和动物模型都将被利用。我们还计划通过基因表达谱和ChIP-on-chip实验来确定这两种途径的下游靶点。这些研究将使我们能够更清楚地定义Wnt信号在细胞和全身代谢中的作用，并可能导致对人类2型糖尿病发病机制有直接影响的结果。对关键组织中Wnt信号的直接操纵可能会转化为2型糖尿病的治疗干预措施。

DESCRIPTION (provided by applicant): There has been much interest in the potential connection between mitochondrial dysfunction and insulin resistance. In our studies to identify novel regulators of mitochondrial biogenesis and function, we have found that Wnt activation in cultured muscle cells induces mitochondrial proliferation and enhances insulin sensitivity, in part through the induction of the adaptor protein insulin receptor substrate-1 (IRS-1). While the Wnt signaling network has been studied primarily in the contexts of cell proliferation, differentiation, and developmental processes, an emerging body of evidence now implicates Wnt signaling in metabolism. In particular, a strong association between allelic variations in Wnt pathway genes and the susceptibility to type 2 diabetes has been documented. We now seek to evaluate the possibility that a functional loss of Wnt signaling can produce insulin resistance in muscle cells. In Aim 1, we will use Wnt antagonists to assess the effect of inhibiting Wnt signaling on mitochondrial physiology and insulin sensitivity in muscle, using both cell culture and animal models. In Aim 2, we will examine the functional interactions between the non-canonical and the canonical Wnt signaling pathways in the context of mitochondrial physiology and insulin sensitivity in muscle. Both cell culture and animal models will be utilized. We also plan to identify the downstream targets of these two pathways by gene expression profiling and ChIP-on-chip experiments. These studies will allow us to more clearly define the role of Wnt signaling in cellular and systemic metabolism, and may lead to results with a direct bearing on the pathogenesis of human type 2 diabetes. A directed manipulation of Wnt signaling in key tissues may potentially translate into therapeutic interventions for type 2 diabetes. PUBLIC HEALTH RELEVANCE: We are studying genes involved in the regulation of mitochondria and exploring their connections to insulin sensitivity. This may lead to information useful for diagnostic or therapeutic applications for type 2 diabetes.