Brown fat dynamics: elucidation of molecular drivers using hibernation as a model

描述(由申请人提供)： 项目摘要肥胖是一个严重且日益严重的公共卫生问题。当卡路里摄入量的增加与代谢活动的增加不能平衡时，它是由于能量动态平衡的损失造成的。棕色脂肪组织(BAT)是一种潜在的减肥器官，因为它专门用于 以热的形式消耗能量。包括地松鼠在内的一年一次的冬眠动物通过在身体脂肪储存和利用的戏剧性极端之间循环，自然地挑战能量动态平衡的传统观点。这些动物在为冬季冬眠做准备时，每年都会经历蝙蝠的肥大，并在整个冬季冬眠中依靠严格控制的非颤抖产热周期。春季出现后，蝙蝠几乎消失，但它在每年秋天重新建立，为下一个冬眠季节做准备。这些时间和职能上的隔离为审查和定义控制蝙蝠招募和活动的监管机制提供了一个非同寻常的机会。我们假设冬眠者使用典型的哺乳动物机制来增加和维持BAT，以及调节它的活动。重要的是，由于冬眠的动力学和要求，冬眠者还提供了一个特殊的、高度复杂的模型系统来解释这些机制。这项R21申请中提出的工作的具体目标是利用现有的组织库，从代表冬眠者一年表型转换关键点的一组精确计时的动物中收集，第一：询问蛋白质组，第二：转录组，与蝙蝠转换相关的质和量变化。这种由冬眠表型提供的独特优势所提供的特征，将为未来调节蝙蝠招募和可逆控制其活动的途径的机制研究奠定必要的基础，并最终将它们作为肥胖症治疗的靶点。

DESCRIPTION (provided by applicant): Project Summary Obesity is a significant and growing public health problem. It results from loss of energy homeostasis when increases in caloric intake are not balanced by elevated metabolic activity. Brown adipose tissue (BAT) is a potential anti-obesity organ because it is specialized to dissipate energy as heat. Circannual hibernators including ground squirrels naturally challenge conventional views of energy homeostasis by cycling between dramatic extremes of body fat storage and utilization. These animals undergo hypertrophy of BAT each year as they prepare for winter hibernation, and depend on tightly-regulated periods of non-shivering thermogenesis throughout winter hibernation. After spring emergence, BAT nearly disappears but it is re- established each fall in preparation for the next hibernation season. These temporal and functional segregations provide an extraordinary opportunity to examine and define regulatory mechanisms controlling BAT recruitment and activity. We hypothesize that hibernators employ typical mammalian mechanisms for increasing and maintaining BAT, as well as for modulating its activity. Importantly, because of the dynamics and demands of hibernation, hibernators also provide an exceptional, highly-elaborated model system in which to elucidate those mechanisms. The specific goals of the work proposed in this R21 application are to exploit an existing tissue bank, collected from a precisely-timed set of animals representing key points in the phenotypic transitions of a hibernator's year, to first: interrogate the proteome and second: the transcriptome, for qualitative and quantitative changes associated with BAT transitions. This characterization, enabled by unique advantages offered by the hibernating phenotype, will form a necessary foundation for future mechanistic studies of pathways that underlie the regulation of BAT recruitment and the reversible control of its activity, and ultimately to harness them as targets for obesity therapy.