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 参与代谢调节的途径和细胞机制 从而提供用于增加能量的治疗靶点 支出和防治肥胖症。拟议的研究计划是一个全面的， 逻辑组织，假设驱动的一系列研究，以检查一种新的机制， 对于能量消耗的基本调节（减少交感神经激活， 在燃料可用性降低的情况下的棕色脂肪组织），这可能有助于 不能通过限制热量来减轻体重。这种模式尤其相关 由于新数据表明，在成人中存在棕色脂肪组织， 非人类的研究表明，该组织的功能量是相反的， 与肥胖有关。 拟议的研究将利用功能神经解剖学和体内 电生理技术来阐明组织和药理学的 神经通路负责葡萄糖缺乏或禁食诱导的减少， 交感神经激活褐色脂肪组织。这三个具体目标将明确测试 关于特定神经化学定义的神经元的功能作用的定义假设 在延髓腹外侧区、下丘脑室旁核和 苍白中缝区在葡萄糖缺乏诱导的能量消耗减少中的作用 棕色脂肪组织了解抑制神经系统的神经通路和机制 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， 代表了朝着开发治疗方法的重要一步， 即使在饮食限制的情况下，也能增加能量消耗， 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.