Neural circuitry responsible for metabolic inhibition of adaptive thermogenesis

项目摘要 这项研究的长期目标是了解神经 参与血管紧张素转换酶代谢调节的途径和细胞机制 能量消耗，从而为增加能量提供治疗靶点 支出和与肥胖作斗争。拟议的研究计划是一项全面的、 逻辑组织的、假设驱动的一系列研究，以检验一种新的机制 对于能量消耗的基本调节(交感神经活动减少 燃料供应减少的情况下的棕色脂肪组织)，这可能有助于 不能通过限制卡路里来减肥。该模型特别适用于 由于新数据显示在成人和临床和非临床人群中存在棕色脂肪组织 非人类的研究表明，这种组织的功能量与之相反 与肥胖有关。 拟议的研究将利用功能、神经解剖学和活体研究。 电生理学技术阐明细胞的组织和药理学 糖代谢或禁食所致脑血管紧张素转换酶降低的神经通路 棕色脂肪组织的交感神经激活。这三个具体目标将清楚地检验 关于特定神经化学定义神经元功能作用的明确假设 在延髓腹外侧部、下丘脑室旁核和 中缝苍白球区葡萄糖代谢引起的能量消耗减少 棕色脂肪组织。了解抑制的神经通路和机制 交感神经流出到棕色脂肪组织将为确定 这些途径的改变如何导致超重和肥胖，以及 代表着朝着发展治疗方法迈出的重要一步 即使面对饮食限制，也要增加能量消耗，从而与 肥胖。

Project Summary The long term objective of this research is to gain an understanding of the neural pathways and cellular mechanisms that are involved in the metabolic regulation of energy expenditure thereby providing therapeutic targets for increasing energy expenditure and combating obesity. The proposed research plan is a comprehensive, logically-organized, hypothesis-driven series of studies to examine a novel mechanism for a fundamental regulation of energy expenditure (decreased sympathetic activation of brown adipose tissue in situations of decreased fuel availability) that may contribute to the inability to lose body weight by caloric restriction. This model is especially relevant since new data demonstrate brown adipose tissue in adult humans and both clinical and non-human studies demonstrate that the functional amount of this tissue is inversely correlated with obesity. The proposed studies will utilize functional neuroanatomical and in vivo electrophysiological techniques to elucidate the organization and pharmacology of the neural pathway responsible for the glucoprivation or fasting-induced decrease in sympathetic activation of brown adipose tissue. The three specific aims will test clearly defined hypotheses on the functional roles of specific neurochemically-defined neurons in the ventrolateral medulla, the paraventricular nucleus of the hypothalamus, and the raphe pallidus area in the glucoprivation-induced decrease in energy expenditure in brown adipose tissue. Understanding the neural pathways and mechanisms that inhibit sympathetic outflow to brown adipose tissue will provide a foundation for determining how alterations in these pathways contribute to overweight and obesity, and will represent an important step towards the development of therapeutic approaches to increase energy expenditure even in the face of dietary restriction and thereby combat obesity.