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：
8664840
负责人：
YOUNG-HWAN JO
金额：
$ 36.32万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8664840
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

项目摘要

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障碍，其特征是体内脂肪过多。肥胖是由于延长的正能量平衡（即能量摄入超过能量消耗）而引起的。尽管尚未明确定义肥胖过度平衡过度平衡的原因，但关键成分位于下丘脑，特别是在弧形核中。下丘脑的弧形核（ARC）对于调节能量平衡至关重要，被认为在外围和中枢神经系统响应的初始传入信号之间起着关键的综合作用。下丘脑黑色皮质素能系统，由位于ARC和黑色素素受体4（MC4R）表达神经元的神经元内的pro-甲状腺素（POMC）和与Agouti相关的肽（AGRP）神经元组成，整个神经元中表达神经元的神经元。 ARC的厌食症POMC神经元对循环信号有反应，并通过释放厌食性黑色素刺激的激素来促进能量消耗。最近的研究表明，POMC神经元至少可以根据神经递质表型和包括瘦素和胰岛素受体在内的受体的表达来分为两个亚群。我们假设这些表型区分反映了重要的功能差异，并且是在两种表型不同的POMC神经元种群之间的相互作用，这是整合外周和中心信号分子所必需的，从而控制了POMC神经元的厌食性结果。在此提案中，我们将确定POMC神经元不同种群之间的新型相互作用如何有助于控制下丘脑神经生理学和能量稳态的调节。我们将对调节3个特定目标的能量平衡的细胞机制提供完全新颖的观点。目标1：确定弧中POMC神经元异质性的程度。 AIM 2：确定POMC神经元的两个不同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。我们将获得的信息将提供对POMC-POMC神经元相互作用的生理后果的新见解。我们的研究还将支持这样一种观念，即在下丘脑开发的早期阶段建立POMC异质性是整体能量平衡的关键因素。因此，拟议的研究将提供对整个黑素性系统神经生物学的新见解，尤其是其在能量平衡控制中的特定作用。