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.

要了解代谢性疾病的病因，包括II型糖尿病，我们必须获得更好 洞悉与葡萄糖代谢相关的神经元电路。 VMH神经元控制全身葡萄糖 通过控制包括胰腺（胰岛素和胰高血糖素）在内的外围器官的代谢。葡萄糖激发 VMH中的（GE）和抑制葡萄糖（GI）神经元已被确定为控制的主要参与者 外周葡萄糖代谢。虽然有共识，即这两个神经元种群都涉及 在全身性葡萄糖代谢中，使细胞受到葡萄糖的激发或抑制的细胞机制 是未知的，这两个神经元的两个亚群是如何同步到达目标组织的 定义不明。我们的建议旨在通过确定这些持久的杰出问题 VMH葡萄糖传感神经元的翻译特征响应葡萄糖水平的变化，这 将其身份决定为GE或GI及其目标部位。我们发表的持续研究支持 到当前的资金期限，涉及的细胞内机制的关键相关性 通过解偶联蛋白2（UCP2）和Dynamin相关蛋白1（DRP1）控制的线粒体动力学 VMH对葡萄糖负荷和葡萄糖稳态的全身控制的反应。这些结果以及我们的 GE神经元的RNASEQ的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为 与线粒体脂肪酸氧化相关 响应葡萄糖水平变化的签名决定了VMH葡萄糖感应的身份 神经元无论是GE还是GI及其靶位点，糖酵解以及脂质氧化 通过线粒体裂变启用GE神经元活性。我们对这些研究的方法涉及 使用可用的转基因动物模型，这将使​​我们能够结合创新和最先进的动物模型 激活，遗传和病毒靶向的神经元中的RNASEQ在内的技术，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心调节提供新的见解。