Energy Homeostasis: GABAergic and Non-GABAergic POMC neurons

下丘脑神经元是神经回路的主要组成部分， 能量平衡弓状核（ARC）中的前阿黑皮素（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起主要作用。在我们 从2012年7月13日到现在，我们已经清楚地证明了 ARC中POMC神经元的分子和神经化学异质性， POMC神经元的亚群直接和间接相互作用的方式是至关重要的， 黑皮质素信号的最终结果。除了这种神经化学异质性， 神经解剖学研究表明，不同的POMC神经元投射到不同的神经元， 目标站点。ARC POMC神经元的这种神经化学和神经解剖学异质性， 结合其广泛的功能剧目，强烈支持有功能的想法， ARC POMC神经元的异质性。正如我们在上一个奖项下的具体目标一样， 完成后，我们现在提出，神经化学不同的POMC亚群， 神经元具有不同的靶器官和功能。 肝脏是过夜禁食和短期禁食的主要葡萄糖供应者。肝 葡萄糖的产生来自于通过异源生殖的从头合成或来自于 通过糖原分解降解肝糖原。这一过程似乎受到 中枢黑皮质素系统例如，ARC POMC神经元投射到肝脏， 出生后POMC神经元的消融升高血糖水平并诱导葡萄糖代谢 不容忍然而，在我们的神经生物学知识中仍然存在着基础性的空白 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 初步研究表明，ARC POMC神经元的亚群通过以下途径支配肝脏： 两个自主神经中枢，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一个问题， POMC神经元投射到肝脏的类型和POMC使用的自主神经回路 神经元调节肝脏葡萄糖的产生。事实上，最近的研究表明， 专门在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、葡萄糖代谢和自发活动 由不同的POMC神经元调控。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 肝脏葡萄糖的产生。在目标1中，我们将彻底检查神经化学物质， ARC POMC神经元投射到肝脏的神经解剖学特性。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 目标2 总之，我们将把光遗传学与病毒介导的Cre递送结合起来， 重组酶基因来实现器官特异性光遗传学调控，这是极具创新性的。正如我们 可以在体内操纵专门的肝脏投射POMC神经元活性， 决议，这将大大扩大我们的能力，探索因果关系之间的 黑皮质素信号传导和肝葡萄糖稳态。

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.