Neurally distributed melanocortinergic control of energy expenditure

能量消耗的神经分布黑皮质能控制

• 批准号: 7409462
• 负责人: Karolina P Skibicka
• 金额: $ 4.1万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7409462
• 关键词: Accounting; Address; Agonist; Animals; Attention; Basic Science; Brain Stem; Brain region; Brown Fat; Cell Nucleus; Cerebrospinal Fluid; Cerebrum; Childhood; Comorbidity; Condition; Data; Diabetes Mellitus; Diet; Disruption; Dose; Eating; Energy Intake; Energy Metabolism; Evaluation; Expenditure; Exposure to; Food; Hand; Heart Rate; Human; Hypothalamic structure; Injection of therapeutic agent; Laboratories; Lead; Leptin; Ligands; Link; Literature; Localized; Location; Maintenance; Marshal; Measurement; Mediating; Mediation; Melanocortin 4 Receptor; Methods; Mus; Mutation; Neuraxis; Neurons; Neuropeptides; Numbers; Obesity; Overweight; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Process; Prosencephalon; Rate; Receptor Signaling; Relative (related person); Research; Research Personnel; Resources; Signal Transduction; Site; Source; System; Techniques; Temperature; Ventricular; base; energy balance; energy density; feeding; hindbrain; human MC4R protein; interest; melanocortin receptor; neural circuit; neurochemistry; paraventricular nucleus; receptor; response

DESCRIPTION (provided by applicant): Due to increasing rates of obesity and its comorbidities, there is tremendous interest in the central nervous system (CNS) control of energy balance. This basic science interest is guided in part by the need to develop effective drugs for the overweight and obese patient. Despite a large literature, our understanding of the circuits and neurochemical receptors that mediate energy balance is still limited. The proposed studies address this limitation by defining the neural circuits that mediate melanocortin's effects on energy expenditure. Disruption in CNS melanocortin receptor (MCR) signaling is the single largest monogenic cause of human obesity. Similarly, animals with disrupted MCR signaling ingest more food and expend less energy. The contribution of MCRs to energy intake control has been investigated intensely. However, much less attention is directed at defining the MCR-containing neural circuits that contribute to energy expenditure. Attention is needed, in part, because the potential contribution of MCR bearing nuclei in different brain regions to energy expenditure is largely unexplored. On the one hand, forebrain ventricular application of MCR agonists, the most common method of delivery, triggers sympathetically mediated expenditure responses that have been attributed to signaling at hypothalamic structures (e.g., the arcuate and paraventricular nuclei). On the other hand, caudal flow of the injected ligands in cerebral spinal fluid makes ligand available to extrahypothalamic sites. Given the widespread distribution of MCRs it is impossible to define which MCR-bearing neurons - among them several hypothalamic and caudal brainstem nuclei- contribute to the observed effects. The aims of my proposal address these limitations. Aim I distinguishes the respective contributions of the hypothalamic and caudal brainstem divisions of the melanocortin system to energetic control under baseline conditions by physiological, as well as neuroanatomical assessments. Aim II uses antagonist treatments to evaluate endogenous melanocortin contributions to the thermogenic responses driven by energy challenges (i.e. cold and diet). The aims use different research strategies - pharmacological, physiological and neuroanatomical - to provide the data needed to critically evaluate the hypothesis that the melanocortin system's contribution to energy expenditure is distributed across spatially distinct regions of the brain.

描述（由申请人提供）：由于肥胖及其合并症的发病率不断增加，人们对中枢神经系统（CNS）能量平衡的控制产生了极大的兴趣。这种基础科学兴趣在一定程度上是出于为超重和肥胖患者开发有效药物的需要。尽管有大量文献，但我们对介导能量平衡的回路和神经化学受体的理解仍然有限。拟议的研究通过定义介导黑皮质素对能量消耗的影响的神经回路来解决这一局限性。中枢神经系统黑皮质素受体 (MCR) 信号传导的破坏是人类肥胖的最大单基因原因。同样，MCR 信号被破坏的动物会摄入更多的食物并消耗更少的能量。 MCR 对能量摄入控制的贡献已得到深入研究。然而，对于定义有助于能量消耗的包含 MCR 的神经回路的关注要少得多。需要引起注意的部分原因是，不同大脑区域的 MCR 承载核对能量消耗的潜在贡献在很大程度上尚未被探索。一方面，前脑室应用 MCR 激动剂（最常见的递送方法）会触发交感神经介导的消耗反应，该反应归因于下丘脑结构（例如弓状核和室旁核）的信号传导。另一方面，注射配体在脑脊液中的尾部流动使配体可到达下丘脑外部位。鉴于 MCR 的广泛分布，不可能确定哪些携带 MCR 的神经元（其中有几个下丘脑和尾部脑干核）对观察到的效应有贡献。我的提案的目的是解决这些限制。目标 I 通过生理学和神经解剖学评估来区分黑皮质素系统的下丘脑和尾部脑干部分对基线条件下的能量控制的各自贡献。 Aim II 使用拮抗剂治疗来评估内源性黑皮质素对能量挑战（即寒冷和饮食）驱动的产热反应的贡献。这些目标使用不同的研究策略——药理学、生理学和神经解剖学——来提供批判性评估黑皮质素系统对能量消耗的贡献分布在大脑不同空间区域的假设所需的数据。