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: 9135814
• 负责人: YOUNG-HWAN JO
• 金额: $ 7.99万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135814
• 关键词: Adult; Body fat; Chronic; Complex; Data; Desire for food; Development; Endorphins; Energy Intake; Energy Metabolism; Epidemic; Equilibrium; Glucose; Glutamate Decarboxylase; Heterogeneity; Homeostasis; Human; Hypothalamic structure; Insulin; Insulin Receptor; Leptin; Litter Size; Melanocortin 3 Receptor; Melanocortin 4 Receptor; Melanocyte stimulating hormone; Metabolic Diseases; Mission; Modeling; Morbidity - disease rate; Mus; Neuraxis; Neurobiology; Neurons; Neurotransmitters; Obesity; Outcome; Output; Overnutrition; Pathogenesis; Peptides; Peripheral; Phenotype; Physiological; Placebo Effect; Play; Population; Pro-Opiomelanocortin; Protein Isoforms; Regulation; Role; Signal Transduction; Signaling Molecule; Site; Staging; Structure of nucleus infundibularis hypothalami; System; Testing; United States National Institutes of Health; Work; cost; energy balance; gamma-Aminobutyric Acid; insight; leptin receptor; melanocortin receptor; mortality; neural circuit; neurophysiology; novel; optogenetics; patch clamp; postsynaptic; receptor expression; relating to nervous system; response; transmission process

DESCRIPTION (provided by applicant): Obesity is a chronic metabolic disorder characterized by an excess of body fat. Obesity results from prolonged positive energy balance (i.e. energy intake exceeding energy expenditure). Although the cause of the excessive positive energy balance in obesity has not been clearly defined, key components reside in the hypothalamus, specifically in the arcuate nucleus. The arcuate nucleus (ARC) of the hypothalamus is critical for regulation of energy balance and is considered to play a key integrative role between the initial afferent signals from the periphery and CNS responses. The hypothalamic melanocortinergic system, composed of proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons located within the ARC and melanocortin receptor type 4 (MC4R)-expressing neurons throughout the neuraxis, is a major regulator of energy homeostasis. Anorexigenic POMC neurons of the ARC respond to circulating signals and contribute to the regulation of energy expenditure by releasing the anorexigenic melanocyte-stimulating hormones. Recent studies have demonstrated that POMC neurons can be divided, at least, into two subpopulations in terms of the neurotransmitter phenotype and the expression of receptors, including leptin and insulin receptors. We hypothesize that these phenotypic distinctions reflect important functional differences and that it is the interplay between two phenotypically distinct populations of POMC neurons that is required for integration of peripheral and central signaling molecules, thus controlling the anorexigenic outcome of POMC neurons. In this proposal, we will determine how novel interactions between distinct populations of POMC neurons contribute to the control of hypothalamic neurophysiology and the regulation of energy homeostasis. We will provide an entirely novel perspective on the cellular mechanisms regulating energy balance in 3 specific aims. Aim 1: Determine the extent of POMC neuron heterogeneity in the ARC. Aim 2: Determine the physiological interactions between two of the distinct subsets of POMC neurons. Aim 3: Determine the network effect of POMC neuron heterogeneity and interaction. The information that we will thereby obtain will provide novel insight into the physiological consequences of POMC-POMC neuron interactions. Our studies will also lend support to the idea that the establishment of POMC heterogeneity during early stages of hypothalamic development is a critical factor for overall energy balance. Hence the proposed studies will provide novel insights into the neurobiology of melanocortin system in general and its specific role in the control of energy balance in particular.

描述（由申请人提供）：肥胖是一种慢性代谢性疾病，其特征是体内脂肪过多。肥胖是由于长期正能量平衡（即能量摄入超过能量消耗）造成的。尽管肥胖中过度正能量平衡的原因尚未明确，但关键成分位于下丘脑，特别是弓状核。下丘脑的弓状核（ARC）对于能量平衡的调节至关重要，被认为在来自外周的初始传入信号和中枢神经系统反应之间发挥着关键的整合作用。下丘脑黑皮质素能系统由位于 ARC 内的阿片黑皮质素原 (POMC) 和刺鼠相关肽 (AgRP) 神经元以及遍布整个神经轴的表达黑皮质素受体 4 (MC4R) 的神经元组成，是能量稳态的主要调节器。 ARC 的厌食 POMC 神经元对循环信号做出反应，并通过释放厌食黑素细胞刺激激素来调节能量消耗。最近的研究表明，根据神经递质表型和受体（包括瘦素和胰岛素受体）的表达，POMC 神经元至少可以分为两个亚群。 我们假设这些表型差异反映了重要的功能差异，并且两个表型不同的 POMC 神经元群体之间的相互作用是外周和中枢信号分子整合所必需的，从而控制 POMC 神经元的厌食结果。在本提案中，我们将确定不同 POMC 神经元群体之间的新颖相互作用如何有助于下丘脑神经生理学的控制和能量稳态的调节。我们将在三个具体目标中提供关于调节能量平衡的细胞机制的全新视角。目标 1：确定 ARC 中 POMC 神经元异质性的程度。目标 2：确定两个不同的 POMC 神经元子集之间的生理相互作用。目标 3：确定 POMC 神经元异质性和相互作用的网络效应。 我们由此获得的信息将为 POMC-POMC 神经元相互作用的生理后果提供新的见解。我们的研究还将支持以下观点：下丘脑发育早期阶段 POMC 异质性的建立是整体能量平衡的关键因素。因此，拟议的研究将为黑皮质素系统的神经生物学及其在能量平衡控制中的具体作用提供新的见解。