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生率不断增加，因此对中枢神经系统（CNS）控制能量平衡产生了极大的兴趣。这种基本的科学兴趣部分是由需要开发有效的药物，超重和肥胖的病人。尽管有大量的文献，我们对调节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影响的神经回路来解决这一限制。中枢神经系统黑皮质素受体（MCR）信号传导的中断是人类肥胖的最大单基因原因。同样，MCR信号被破坏的动物摄取更多的食物，消耗更少的能量。MCR对能量摄入控制的贡献已经被深入研究。然而，很少有人关注定义有助于能量消耗的含MCR的神经回路。需要注意的是，部分原因是在不同的大脑区域的MCR轴承核的能量消耗的潜在贡献在很大程度上是未开发的。一方面，MCR激动剂的前脑心室应用（最常见的递送方法）触发交感神经介导的消耗反应，其归因于下丘脑结构处的信号传导（例如，弓状核和室旁核）。另一方面，注射的配体在脑脊液中的尾流使配体可用于下丘脑外部位。鉴于MCR的广泛分布，不可能确定哪些携带MCR的神经元（其中包括几个下丘脑和尾侧脑干核团）对观察到的效应有贡献。我的建议旨在解决这些限制。目的我区分各自的贡献下丘脑和尾侧脑干分区的黑皮质素系统的能量控制在基线条件下的生理，以及神经解剖学评估。目的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-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空间不同区域的假设所需的数据。