Energy Homeostasis: GABAergic and Non-GABAergic POMC Neurons

描述(申请人提供)：肥胖是一种慢性代谢紊乱，其特征是体内脂肪过多。肥胖是由于长时间的正能量平衡(即能量摄入超过能量消耗)造成的。虽然肥胖症过度正能量平衡的原因尚未明确，但关键成分存在于下丘脑，特别是弓状核。下丘脑的弓状核(ARC)对能量平衡的调节至关重要，被认为在最初的外周传入信号和中枢神经系统反应之间起着关键的整合作用。下丘脑黑素皮质素能系统由位于ARC内的前阿片黑素皮质素(POMC)和刺鼠相关肽(AgRP)神经元以及贯穿神经轴的表达黑素皮质素受体4(MC4R)的神经元组成，是能量平衡的主要调节因子。ARC的缺氧性POMC神经元对循环信号作出反应，并通过释放厌氧性黑素细胞刺激激素来调节能量消耗。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而分为两个亚群。我们假设，这些表型差异反映了重要的功能差异，正是两个表型不同的POMC神经元群体之间的相互作用，才是整合外周和中枢信号分子所必需的，从而控制POMC神经元的厌食结果。在这项提议中，我们将确定不同POMC神经元群体之间的新的相互作用如何有助于控制下丘脑的神经生理学和调节能量稳态。我们将提供一个全新的视角，在三个特定的目标中调节能量平衡的细胞机制。目的1：确定ARC内POMC神经元的异质性程度。目的2：确定POMC神经元两个不同亚群之间的生理相互作用。目的3：确定POMC神经元的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。我们的研究也将支持这一观点，即下丘脑发育早期POMC异质性的建立是整体能量平衡的关键因素。因此，拟议的研究将为黑素皮质素系统的神经生物学提供新的见解，特别是它在能量平衡控制中的特殊作用。

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.