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

棕色脂肪动力学：以冬眠为模型阐明分子驱动因素

• 批准号: 8282994
• 负责人: SANDRA L MARTIN
• 金额: $ 26.61万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282994
• 关键词: Abbreviations; Animals; Biological Models; Body Temperature; Body fat; Body mass index; Brown Fat; Data; Energy Intake; Equilibrium; Fluorescent Dyes; Foundations; Future; Gel; Gene Expression Profile; Goals; Heating; Hibernation; Homeostasis; Hypertrophy; Label; Liquid Chromatography; Mass Spectrum Analysis; Metabolic; Methods; Modeling; Molecular; Names; Obesity; Organ; Pathway interactions; Pattern; Peptides; Phase; Phenotype; Physiological; Post-Translational Protein Processing; Preparation; Proteins; Proteome; Public Health; RNA; Recruitment Activity; Regulation; Regulatory Pathway; Seasons; Spermophilus; Staging; Temperature; Thermogenesis; Time; Tissue Banking; Tissue Banks; Tissue Extracts; Tissues; Work; base; falls; gel electrophoresis; novel; segregation; tandem mass spectrometry; two-dimensional

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. PUBLIC HEALTH RELEVANCE: Project Narrative Obesity is a significant health problem in the US. It results from the loss of body weight homeostasis that occurs when incoming calories exceed daily energy requirements. Brown adipose tissue (BAT) is specialized to dissipate calories in the form of heat, thus making it an attractive target for novel approaches in obesity control. Mammalian hibernators recruit large amounts of BAT each fall in preparation for winter hibernation which then atrophies in spring. In addition, the activity of this augmented BAT is precisely controlled t orchestrate the dramatic oscillations between low and high metabolism that characterize the hibernation season. Our experiments to define the molecular alterations that underlie these phenotypic cycles in hibernation will provide novel insights to facilitate exploitation of BAT in human obesity control.

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。 公共卫生相关性： 肥胖项目在美国是一个严重的健康问题。当摄入的卡路里超过每日的能量需求时，体重的动态平衡就会减少。棕色脂肪组织(BAT)专门以热量的形式分散卡路里，因此成为控制肥胖的新方法的一个有吸引力的目标。哺乳动物冬眠者每年秋天都会招募大量的蝙蝠，为冬季冬眠做准备，然后在春天冬眠。此外，这种增强型蝙蝠的活动受到精确控制，以协调冬眠季节特有的低代谢和高代谢之间的戏剧性振荡。我们的实验确定了冬眠中这些表型周期背后的分子变化，这将为利用BAT控制人类肥胖提供新的见解。