Mitochondrial dynamics in VMH neurons control glucose metabolism

VMH 神经元的线粒体动力学控制葡萄糖代谢

• 批准号: 10220953
• 负责人: Sabrina Diano
• 金额: $ 51.13万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220953
• 关键词: Address; Adult; Agreement; Animal Model; Brain; CRISPR/Cas technology; Cell Nucleus; Cells; Confocal Microscopy; Consensus; Data; Deoxyglucose; Dynamin; Electron Microscopy; Electrons; Enhancers; Enzymes; Etiology; FOS gene; Funding; Gene Expression Profile; Genes; Genetic; Genetically Modified Animals; Glucagon; Glucokinase; Glucose; Glycolysis; Grant; Hypoglycemia; Hypothalamic structure; Insulin; Lipids; Liver; Mediating; Metabolic; Metabolic Diseases; Microscopic; Mitochondria; Mus; Muscle; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Pattern; Peripheral; Population; Process; Proteins; Publishing; Role; Site; Structure of beta Cell of islet; System; Techniques; Testing; Tissues; UCP2 protein; Viral; blood glucose regulation; cellular targeting; experimental study; fatty acid oxidation; glucose metabolism; glucose sensor; hindbrain; innovation; insight; lipid metabolism; mind control; neuronal circuitry; novel; oxidation; parabrachial nucleus; response; transcriptome sequencing; treatment strategy; ventromedial hypothalamic nucleus

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.

为了了解代谢紊乱（包括 II 型糖尿病）的病因，我们必须更好地了解代谢紊乱的病因。 深入了解与葡萄糖代谢相关的神经元回路。 VMH 神经元控制全身葡萄糖 通过控制包括胰腺在内的外周器官（胰岛素和胰高血糖素）来进行新陈代谢。葡萄糖兴奋型 VMH 中的 (GE) 和葡萄糖抑制 (GI) 神经元已被确定为控制 外周葡萄糖代谢。虽然人们一致认为这两个神经元群都参与其中 在全身葡萄糖代谢中，使细胞被葡萄糖兴奋或抑制的细胞机制 目前尚不清楚，这两个神经元亚群如何同步发挥作用，到达其目标组织是未知的 定义不明确。我们的提案旨在通过确定以下问题来解决这些长期存在的悬而未决的问题 VMH 葡萄糖感应神经元响应葡萄糖水平变化的翻译特征 决定它们的身份（GE 或 GI）以及它们的目标位点。我们已发表和正在进行的研究支持 到目前的资助期限，揭示了细胞内机制的至关重要的相关性，涉及 线粒体动力学由解偶联蛋白 2 (UCP2) 和动力相关蛋白 1 (DRP1) 控制 VMH 对葡萄糖负荷的反应和葡萄糖稳态的全身控制。这些结果，连同我们的 GE 神经元的 RNAseq 数据揭示了与脂质和葡萄糖代谢相关的基因，以及我们的结果 表明 VMH 神经元中 UCP2 依赖性 DRP1 介导的线粒体裂变的激活是 与线粒体脂肪酸氧化相关，推动了我们的假设，即特定的翻译 响应葡萄糖水平变化的特征决定了 VMH 葡萄糖传感的特性 神经元（无论是 GE 还是 GI）及其靶位点、糖酵解和脂质氧化 通过线粒体裂变驱动 GE 神经元活动。我们进行这些研究的方法包括 使用现有的转基因动物模型，这将使​​我们能够将创新和最先进的技术结合起来 技术，包括神经元激活时的 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。 这些研究的完成将为葡萄糖代谢的中央调节提供新的见解。