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

描述（由申请人提供）： 肥胖是一个重要的和日益严重的公共卫生问题。当热量摄入的增加没有被代谢活动的增加所平衡时，它是能量稳态丧失的结果。棕色脂肪组织（BAT）是一种潜在的抗肥胖器官，因为它专门用于 以热量的形式耗散能量。包括地松鼠在内的一年四季冬眠动物通过在体内脂肪储存和利用的极端状态之间循环，自然地挑战了能量平衡的传统观点。这些动物每年在准备冬眠时都会经历BAT的肥大，并且在整个冬眠期间依赖于严格调节的非颤抖产热期。春天出现后，蝙蝠几乎消失，但它是重新建立每年秋天在准备下一个冬眠季节。这些时间和职能上的分离为审查和界定控制最佳可得技术人员招募和活动的监管机制提供了一个难得的机会。我们假设，冬眠动物采用典型的哺乳动物机制，增加和维持BAT，以及调节其活动。重要的是，由于冬眠的动力学和需求，冬眠动物也提供了一个特殊的，高度复杂的模型系统来阐明这些机制。在这个R21应用程序中提出的工作的具体目标是利用现有的组织库，从一组精确定时的动物中收集，这些动物代表冬眠动物一年中表型转变的关键点，首先：询问蛋白质组，其次：转录组，与BAT转变相关的定性和定量变化。这种表征，使冬眠表型提供的独特优势，将形成一个必要的基础，为未来的机制研究的途径，调节BAT的招聘和可逆控制其活动，并最终利用它们作为肥胖治疗的目标。

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.