Mitochondrial dynamics in VMH neurons control glucose metabolism

为了了解代谢紊乱的病因，包括II型糖尿病，我们必须更好地获得 深入了解与葡萄糖代谢相关的神经回路。VMH神经元控制全身血糖 通过控制包括胰腺在内的外周器官(胰岛素和胰高血糖素)来代谢。葡萄糖刺激 VMH中的(GE)和葡萄糖抑制(GI)神经元被认为是控制 外周葡萄糖代谢。虽然有一个共识是这两个神经元群体都参与了 在全身性葡萄糖代谢中，使细胞能够被葡萄糖激活或抑制的细胞机械。 以及这两个神经元亚群如何同时发挥作用，到达它们的目标组织是未知的 定义不明确。我们的建议旨在通过确定 VMH葡萄糖感受神经元对葡萄糖水平变化的翻译特征 指定他们的身份，作为GE或GI，以及他们的目标站点。我们已发表和正在进行的研究支持 到目前的资助期，揭示了细胞内机制的关键相关性，包括 解偶联蛋白2和动力蛋白相关蛋白1控制的线粒体动力学 VMH对葡萄糖负荷的反应和系统对葡萄糖稳态的控制。这些结果，连同我们的 GE神经元RNAseq揭示与脂肪和葡萄糖代谢相关的基因的数据，以及我们的结果 结果表明，VMH神经元中UCP2依赖的Drp1介导的线粒体分裂的激活是 与线粒体脂肪酸氧化有关，支持了我们的假设，即一种特定的翻译 响应于血糖水平变化的签名指示VMH葡萄糖传感的身份 无论是GE还是GI的神经元及其靶点和糖酵解，以及脂质氧化 通过线粒体分裂驱动GE神经元的活动。我们对这些研究的方法涉及 使用现有的转基因动物模型，使我们能够结合创新和最先进的 技术包括激活时神经元中的RNAseq，遗传和病毒靶向，CRISPR/Cas9，iDISCO 技术，以及共聚焦和电子显微镜检查。 这些研究的完成将对葡萄糖代谢的中枢调控提供新的见解。

To understand the etiology of metabolic disorders, including type II diabetes, it is essential that we gain better insight into the neuronal circuitry related to glucose metabolism. VMH neurons control systemic glucose metabolism via control of peripheral organs including the pancreas (insulin and glucagon). Glucose-excited (GE) and glucose-inhibited (GI) neurons in the VMH have been identified as major players in the control of peripheral glucose metabolism. While there is a consensus that both of these neuronal populations are involved in systemic glucose metabolism, the cellular machinery that enables cells to be excited or inhibited by glucose is unknown and how these 2 subpopulations of neurons, functioning synchronously, reach their target tissues is ill-defined. Our proposal aims to address these long-lasting outstanding questions by identifying the translational signature of VMH glucose sensing neurons in response to changes in glucose levels which dictate their identity, as either GE or GI, and their target sites. Our published and ongoing studies supported by the current funding period unmasked the crucial relevance of the intracellular mechanism involving mitochondrial dynamics controlled by uncoupling protein 2 (UCP2) and dynamin-related protein 1 (DRP1) in VMH response to glucose load and systemic control of glucose homeostasis. These results, together with our data on the RNAseq of GE neurons unmasking genes relevant to lipid and glucose metabolism, and our results showing that the activation of UCP2-dependent DRP1-mediated mitochondrial fission in VMH neurons is associated with mitochondrial fatty acid oxidation, gave impetus to our hypothesis that a specific translational signature in response to changes in glucose levels dictate the identity of the VMH glucose sensing neurons whether they are GE or GI and their target sites and that glycolysis, and that lipid oxidation drive GE neuronal activity enabled by mitochondrial fission. Our approach to these studies involves the use of available genetically modified animal models that will allow us to combine innovative and state-of-the-art techniques including RNAseq in neurons while activated, genetic and viral targeting, CRISPR/Cas9, the iDISCO technique, together with the confocal- and electron microscopic examinations. The completion of these studies will give new insights in the central regulation of glucose metabolism.