Alcohol Consumption and Brown Adipose Tissue

描述（由申请人提供）：这个探索性项目将检验长期饮酒损害棕色脂肪组织（BAT）产热能力的假设，并且这种损害与酒精对BAT类维生素a代谢的影响有关。该项目有两个具体目标，第一个目的是评估与长期饮酒有关的BAT功能损伤，第二个目的是提供酒精对该组织影响的机制见解。本项目的研究成果将对酒精中毒、BAT生理、类视黄醇稳态研究等3个研究领域具有广泛意义。BAT在成人中具有生理功能的概念代表了BAT研究领域的范式转变，并导致对这一迄今未被充分认识的组织的兴趣增加。我们的初步数据显示，长期饮酒与体温维持失调以及BAT质量显著下降有关。在具体目标1中，将系统地研究慢性饮酒对BAT产热的功能后果。通过一系列的酒精喂养研究，我们将评估酒精喂养对BAT形态和功能的影响。酒精喂养小鼠的产热能力将使用两种既定技术进行测试：对寒冷暴露的反应性和对去甲肾上腺素的反应性。我们希望确定长期饮酒对成年小鼠BAT的产热能力有负面影响。特异性Aim 1的目的是表征酒精摄食对BAT功能的影响，而特异性Aim 2的目的是提供对这种影响的机制洞察。具体而言，在Specific Aim 2中，我们将检验酒精诱导的类视黄醇代谢失调导致酒精诱导的BAT生理改变的假设。这一假设来源于类维生素a对BAT分化和功能的既定影响，以及我们的初步数据表明，酒精喂养小鼠的BAT改变了组织中类维生素a的水平，以及类维生素a代谢重要基因的基因表达水平的变化。我们计划对酒精喂养小鼠BAT中的类维生素a代谢进行全面分析；我们还将进行酒精喂养实验，其中改变了饮食中的类维生素a含量。我们期望从这些实验中获得的数据将证实我们的假设，即饮酒会破坏BAT类维生素a的稳态，从而影响BAT的功能。综上所述，本R21申请中提出的研究将探索一个新概念，即长期饮酒通过影响BAT影响身体产生热量的能力。关于这些创新假设产生的数据将影响关于酒精消费对肝脏以外组织（特别是BAT）影响的一般概念，并提供对这些变化的机制理解。

DESCRIPTION (provided by applicant): This exploratory project will test the hypothesis that chronic alcohol consumption impairs the thermogenic capacity of brown adipose tissue (BAT), and that this impairment is associated with alcohol's effect on BAT retinoid metabolism. The project has two Specific Aims, the first is designed to assess the functional impairment associated with chronic alcohol consumption on BAT, and the second will provide mechanistic insight into the effects of alcohol in this tissue. The results of this project will be of broad significance to 3 research areas: research on alcoholism, BAT physiology, and retinoid homeostasis. The concept that BAT has physiological functions in adult humans represents a paradigm shift in the field of BAT research, and has led to an increased interest in this hitherto underappreciated tissue. Our preliminary data reveal that chronic alcohol consumption is associated with a dysregulation of body temperature maintenance, as well as a very marked decrease in BAT mass. In Specific Aim 1 the functional consequences of chronic alcohol consumption on BAT thermogenesis will be systematically investigated. Through a series of alcohol-feeding studies, we will assess the effects of alcohol-feeding on BAT morphology and function. The thermogenic capacity of alcohol-fed mice will be tested using 2 established techniques: responsiveness to cold exposure, and responsiveness to a norepinehprine challenge. We expect to establish that chronic alcohol consumption has a negative impact on the thermogenic capacity of BAT in adult mice. While Specific Aim 1 is designed to characterize the effect that alcohol feeding has on BAT function, Specific Aim 2 is designed to provide a mechanistic insight into this effect. Specifically, in Specific Aim 2 we will test the hypothesis tat alcohol-induced dysregulation of retinoid metabolism contributes to alcohol- induced alterations in BAT physiology. This hypothesis has its origins in the established effects that retinoids have on BAT differentiation and function, as well as our preliminary data which indicates that BAT of alcohol-fed mice has altered tissue retinoid levels, as well as changes in the gene expression levels of genes important in retinoid metabolism. We plan to undertake a comprehensive analysis of retinoid metabolism in BAT of alcohol-fed mice; we will also perform alcohol-feeding experiments in which the dietary retinoid content has been altered. We expect that the data obtained from these experiments will confirm our hypothesis that alcohol consumption disrupts BAT retinoid homeostasis, with a consequent effect on BAT function. In summary, the research proposed in this R21 application will explore the novel concept that chronic alcohol consumption affects the body's ability to produce heat through its effect on BAT. The data generated regarding these innovative hypotheses will impact general concepts regarding the effects of alcohol consumption on tissues other than the liver (specifically BAT), as well as provide mechanistic understanding of these changes.