Energy Homeostasis: GABAergic and Non-GABAergic POMC neurons

能量稳态：GABA 能和非 GABA 能 POMC 神经元

• 批准号: 9770833
• 负责人: YOUNG-HWAN JO
• 金额: $ 46.37万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-13 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770833
• 关键词: Ablation; Appetite Stimulants; Award; Blood Glucose; Calcium; Cells; Chimeric Proteins; DNA cassette; Dependovirus; Diabetes Mellitus; Energy Intake; Energy Metabolism; Enhancers; Enterobacteria phage P1 Cre recombinase; Equilibrium; Fasting; Foundations; Genes; Genetically Engineered Mouse; Gluconeogenesis; Glucose; Glucose Intolerance; Hepatic; Heterogeneity; Homeostasis; Hyperglycemia; Hypothalamic structure; Induced Mutation; Knowledge; Liver; Liver Glycogen; Maps; Mediating; Metabolic syndrome; Modeling; Molecular; Motor Activity; Neuroanatomy; Neurobiology; Neurons; Nutrient; Obesity; Opioid; Organ; Outcome; Physiological; Play; Pro-Opiomelanocortin; Process; Proteins; Regulation; Role; Signal Transduction; Site; Spinal Cord Column; Structure of nucleus infundibularis hypothalami; System; Viral; Wheat Germ Agglutinins; blood glucose regulation; dorsal motor nucleus; glucose metabolism; glucose production; glycogenolysis; in vivo; innovation; liver metabolism; neural circuit; neurochemistry; novel therapeutic intervention; optogenetics; postnatal; public health relevance; response; sensor; temporal measurement

The hypothalamic neurons are major components of the neural circuits that control energy homeostasis. Proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) play a major role in regulating energy intake, energy expenditure, and glucose metabolism. In our studies under the previous award from July 13, 2012 to present, we have clearly demonstrated molecular and neurochemical heterogeneity of POMC neurons in the ARC and that distinct subpopulations of POMC neurons directly and indirectly interact in a manner that is critical to the net outcome of the melanocortin signaling. In addition to this neurochemical heterogeneity, neuroanatomical studies have revealed that distinct sets of POMC neurons project to different target sites. This neurochemical and neuroanatomical heterogeneity of ARC POMC neurons, combined with their broad functional repertoire, strongly support the idea that there is functional heterogeneity of ARC POMC neurons. As our specific aims under the previous award have been completed, we now propose that neurochemically distinct subpopulations of POMC neurons have distinct target organs and functions. The liver is the main glucose supplier in overnight fasting and short term fasting. Hepatic glucose production results either from de novo synthesis via gluconeogenesis or from degradation of hepatic glycogen via glycogenolysis. This process appears to be regulated by the central melanocortin system. For instance, ARC POMC neurons project to liver and postnatal ablation of POMC neurons elevates blood glucose levels and induces glucose intolerance. However, there still exist foundational gaps in our knowledge of the neurobiology and neuroanatomy of the central melanocortin system that regulates liver metabolism. Our preliminary studies show that a subpopulation of ARC POMC neurons innervate liver through two autonomic centers, including the intermediolateral cell column of the spinal cord and the dorsal motor nucleus of the vagus. These neuroanatomical studies raise questions as to what types of POMC neurons project to liver and which autonomic circuits are used by POMC neurons to regulate hepatic glucose production. In fact, recent studies with genetically engineered mice that have induced mutations exclusively in POMC neurons have demonstrated that energy intake, energy expenditure, glucose metabolism, and locomotor activity are regulated by distinct sets of POMC neurons. As there exist liver-projecting ARC POMC neurons, we hypothesize that these liver-projecting ARC POMC neurons play a key role in the regulation of hepatic glucose production. In Aim 1, we will thoroughly examine the neurochemical and neuroanatomical identity of ARC POMC neurons projecting to liver. And then we will explore the physiological impact of liver-projecting POMC neuron stimulation on hepatic glucose production in Aim 2. In summary, we will incorporate optogenetics with viral-mediated delivery of the Cre recombinase gene to achieve organ-specific optogenetic control that is highly innovative. As we can manipulate exclusively liver-projecting POMC neuron activity in vivo with high temporal resolution, this will significantly expand our capability to probe the causal relationship between the melanocortin signaling and hepatic glucose homeostasis.

下丘脑神经元是控制神经回路的主要组成部分 能量平衡。弓状核(ARC)中前阿片黑素皮质素(POMC)神经元的作用 在调节能量摄入、能量消耗和葡萄糖代谢方面发挥重要作用。在我们的 从2012年7月13日到现在，根据上一次获奖的研究，我们清楚地表明 弓状回POMC神经元的分子和神经化学异质性 POMC神经元亚群直接或间接相互作用对 黑素皮质素信号的最终结果。除了这种神经化学异质性之外， 神经解剖研究表明，不同组的POMC神经元投射到不同的 目标站点。ARC POMC神经元的这种神经化学和神经解剖学的异质性， 结合他们广泛的功能曲目，强烈支持有功能的 ARC POMC神经元的异质性。正如我们在上一次颁奖中的具体目标 已经完成，我们现在提出POMC的神经化学亚群 神经元有不同的靶器官和功能。 肝脏是隔夜禁食和短期禁食的主要葡萄糖供应者。肝脏 葡萄糖的产生要么是通过糖异生作用进行从头合成，要么是通过 肝糖原通过糖原分解而降解。这一过程似乎受到 中枢黑素皮质素系统。例如，ARC POMC神经元投射到肝脏和 生后消融POMC神经元可升高血糖水平并诱导血糖 不宽容。然而，我们对神经生物学的认识还存在着基础性的空白。 以及调节肝脏新陈代谢的中枢黑素皮质素系统的神经解剖学。我们的 初步研究表明，ARC POMC神经元的一个亚群通过 两个自主神经中心，包括脊髓的中间外侧细胞柱和 迷走神经背侧运动核。这些神经解剖学研究提出了这样一个问题： 投射到肝脏的POMC神经元的类型以及POMC使用哪些自主神经回路 神经元调节肝脏葡萄糖的产生。事实上，最近对遗传基因的研究 仅在POMC神经元中诱导突变的工程小鼠已经证明 能量摄入、能量消耗、葡萄糖代谢和运动活动 由不同的POMC神经元组调控。由于存在投射肝脏的ARC POMC神经元， 我们推测这些投射肝脏的ARC POMC神经元在调节中起关键作用。 肝脏葡萄糖的产生。在目标1中，我们将彻底检查神经化学和 投射到肝脏的ARC POMC神经元的神经解剖学特征。然后我们将探索 刺激肝脏投射POMC神经元对肝脏葡萄糖产生的生理影响 在目标2中。 总而言之，我们将把光遗传学与病毒介导的CRE传递结合起来 重组酶基因实现器官特异性光遗传控制具有很高的创新性。因为我们 可以在体内高时程独占操纵投射肝脏的POMC神经元的活动 解决方案，这将极大地扩展我们探索 黑素皮质素信号与肝脏葡萄糖动态平衡。