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: 9493040
• 负责人: YOUNG-HWAN JO
• 金额: $ 33.4万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9493040
• 关键词: Ablation; Appetite Stimulants; Award; Blood Glucose; 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; 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; 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; interest; liver metabolism; neural circuit; neurochemistry; novel therapeutic intervention; optogenetics; postnatal; public health relevance; relating to nervous system; response; 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 能量稳态。弧形核（ARC）中的肌曲霉素（POMC）神经元 在调节能量摄入，能量消耗和葡萄糖代谢方面的主要作用。在我们的 根据2012年7月13日至现在的先前奖项的研究，我们已经清楚地证明了 POMC神经元中的分子和神经化学异质性，并且不同 POMC神经元的亚群直接和间接相互作用，以对 黑色皮质素信号传导的净结果。除了这种神经化学异质性， 神经解剖学研究表明，不同的POMC神经元集对不同 目标站点。 ARC POMC神经元的神经化学和神经解剖异质性， 结合其广泛的功能曲目，强烈支持有功能的想法 ARC POMC神经元的异质性。作为我们先前奖项的具体目标 已完成，我们现在建议神经化学上不同的POMC亚群 神经元具有不同的靶器官和功能。 肝脏是一夜禁食和短期禁食的主要葡萄糖供应商。肝 葡萄糖的产生是通过糖异生的从头合成的，或 通过糖原分解肝糖原的降解。这个过程似乎由 中央黑色皮质素系统。例如，ARC POMC神经元向肝脏和 POMC神经元的产后消融升高血糖水平并诱导葡萄糖 不宽容。但是，我们对神经生物学的了解仍然存在基本差距 调节肝脏代谢的中央黑色皮质素系统的神经解剖学。我们的 初步研究表明，ARC POMC神经元的亚群通过 两个自主中心，包括脊髓的中间外侧细胞柱和 迷走神经的背运动核。这些神经解剖学研究提出了有关什么的问题 POMC神经元的类型向肝脏项目以及POMC使用哪些自主电路 神经元调节肝葡萄糖的产生。实际上，最近对遗传学的研究 已在POMC神经元中仅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性是 由不同的POMC神经元组调节。由于存在肝脏投射弧神经元， 我们假设这些肝脏预测弧神经元在调节中起关键作用 肝葡萄糖的产生。在AIM 1中，我们将彻底检查神经化学和 投射给肝脏的电弧POMC神经元的神经解剖学身份。然后我们将探索 肝运动POMC神经元刺激对肝葡萄糖产生的生理影响 在目标2中。 总而言之，我们将与病毒介导的CRE递送的光遗传学合并 重组酶基因以实现高度创新的器官特异性光遗传控制。像我们 可以在体内独家操纵POMC神经元活性，并具有较高时间的体内 解决方案，这将大大扩展我们探究因果关系的能力 黑色皮质素信号传导和肝葡萄糖稳态。