Neurally distributed melanocortinergic control of energy expenditure

描述(由申请人提供)：由于肥胖率及其并发症的增加，人们对中枢神经系统(CNS)控制能量平衡产生了极大的兴趣。这种基本的科学兴趣在一定程度上是因为需要为超重和肥胖患者开发有效的药物。尽管有大量文献，但我们对调节能量平衡的回路和神经化学受体的了解仍然有限。拟议中的研究通过定义神经回路来调节黑素皮质素对能量消耗的影响，从而解决了这一局限性。中枢神经系统黑素皮质素受体(MCR)信号的中断是人类肥胖的最大单基因原因。同样，MCR信号中断的动物摄入更多的食物，消耗更少的能量。MCRs对能量摄入控制的贡献已被深入研究。然而，对于定义有助于能量消耗的含有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核团对能量消耗的潜在贡献在很大程度上还没有被探索。一方面，前脑室应用MCR激动剂这一最常见的给药方法，会触发交感神经介导的支出反应，这种反应被归因于下丘脑结构(如弓状核和室旁核)的信号传递。另一方面，注射的配体在脑脊液中的尾部流动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脑干尾侧核--参与了观察到的效应。我的提案的目的是解决这些限制。目的通过生理学和神经解剖学评估，区分黑素皮质素系统的下丘脑和尾侧脑干在基线条件下对能量控制的各自贡献。目的II使用拮抗剂治疗来评估内源性黑素皮质素在能量挑战(即寒冷和饮食)驱动的生热反应中的作用。这些研究的目的是使用不同的研究策略--药理学、生理学和神经解剖学--提供必要的数据，以批判性地评估黑素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。

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.