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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

基本信息

批准号：
10405501
负责人：
Sabrina Diano
金额：
$ 50.44万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405501
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

项目摘要

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.

要了解代谢紊乱的病因，包括II型糖尿病，我们必须获得更好的深入了解与葡萄糖代谢相关的神经回路。VMH神经元控制全身葡萄糖通过控制包括胰腺（胰岛素和胰高血糖素）在内的外周器官的代谢。葡萄糖激发的 (GE)和葡萄糖抑制（GI）神经元在VMH已被确定为控制的主要球员，外周葡萄糖代谢虽然有一个共识，这两个神经元群体参与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还不清楚，这两个神经元亚群如何同步发挥作用，到达它们的靶组织，定义不清我们的建议旨在通过确定 VMH葡萄糖敏感神经元对葡萄糖水平变化的响应，决定了他们的身份，无论是GE或GI，以及他们的目标网站。我们已发表和正在进行的研究支持在目前的资助期内，揭示了细胞内机制的关键相关性，解偶联蛋白2（UCP 2）和动力蛋白相关蛋白1（DRP 1）控制的线粒体动力学 VMH对葡萄糖负荷的反应和葡萄糖稳态的系统控制。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，这表明，在VMH神经元中，UCP 2依赖性DRP 1介导的线粒体分裂的激活是与线粒体脂肪酸氧化相关，推动了我们的假设，即一个特定的翻译响应于葡萄糖水平变化的特征指示VMH葡萄糖感测的身份神经元无论是GE或GI和他们的目标网站和糖酵解，以及脂质氧化通过线粒体分裂驱动GE神经元活动。我们对这些研究的方法涉及使用现有的转基因动物模型，使我们能够将联合收割机创新和最先进的技术结合起来，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，连同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枢调节提供新的见解。