Energy Homeostasis: GABAergic and Non-GABAergic POMC neurons

能量稳态：GABA 能和非 GABA 能 POMC 神经元

基本信息

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
项目类别：
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

项目摘要

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。弓状核 (ARC) 中的阿黑皮素原 (POMC) 神经元发挥作用在调节能量摄入、能量消耗和葡萄糖代谢中发挥重要作用。在我们的从2012年7月13日至今，我们已经清楚地证明了上一奖项的研究 ARC 中 POMC 神经元的分子和神经化学异质性以及不同的 POMC 神经元亚群直接和间接地相互作用，其方式对于黑皮质素信号传导的最终结果。除了这种神经化学异质性之外，神经解剖学研究表明，不同的 POMC 神经元组投射到不同的区域目标站点。 ARC POMC 神经元的神经化学和神经解剖学异质性，结合其广泛的功能库，强烈支持以下观点：功能性 ARC POMC 神经元的异质性。由于我们在上一个奖项下的具体目标已经已经完成，我们现在提出神经化学上不同的 POMC 亚群神经元具有不同的靶器官和功能。肝脏是隔夜禁食和短期禁食的主要葡萄糖供应者。肝的葡萄糖的产生要么来自通过糖异生的从头合成，要么来自通过糖原分解作用降解肝糖原。这个过程似乎是由中枢黑皮质素系统。例如，ARC POMC 神经元投射到肝脏和出生后 POMC 神经元消融会升高血糖水平并诱导血糖升高不宽容。然而，我们对神经生物学的了解仍然存在基础差距以及调节肝脏代谢的中枢黑皮质素系统的神经解剖学。我们的初步研究表明 ARC POMC 神经元亚群通过以下方式支配肝脏两个自主神经中心，包括脊髓的中间外侧细胞柱和迷走神经背运动核。这些神经解剖学研究提出了以下问题： POMC 神经元投射到肝脏的类型以及 POMC 使用哪些自主神经回路神经元调节肝葡萄糖的产生。事实上，最近的基因研究已经证明，仅在 POMC 神经元中诱导突变的工程小鼠能量摄入、能量消耗、葡萄糖代谢和运动活动由不同的 POMC 神经元组调节。由于存在肝脏投射的 ARC POMC 神经元，我们假设这些肝脏投射的 ARC POMC 神经元在调节中发挥关键作用肝葡萄糖的产生。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性。然后我们将探索肝脏投射 POMC 神经元刺激对肝葡萄糖产生的生理影响在目标 2 中。总之，我们将把光遗传学与病毒介导的 Cre 递送结合起来重组酶基因实现器官特异性光遗传学控制，具有高度创新性。正如我们可以在体内专门操纵肝脏投射的 POMC 神经元活动，具有高时间分辨率，这将显着扩展我们探索之间因果关系的能力黑皮质素信号传导和肝葡萄糖稳态。