Alcohol Consumption and Brown Adipose Tissue

描述（由申请人提供）：该探索性项目将检验以下假设：长期饮酒会损害棕色脂肪组织（BAT）的产热能力，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，第一个旨在评估与长期饮酒相关的BAT功能障碍，第二个将提供酒精对该组织影响的机制见解。该项目的结果将对3个研究领域具有广泛意义：酒精中毒，BAT生理学和维甲酸稳态研究。BAT在成年人中具有生理功能的概念代表了BAT研究领域的范式转变，并导致了对这种迄今为止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质量非常显著的减少有关。在具体目标1中，将系统地研究长期饮酒对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。将使用2种已建立的技术检测酒精喂养小鼠的产热能力：对冷暴露的反应性和对去甲肾上腺素激发的反应性。我们希望建立长期饮酒对成年小鼠BAT的产热能力有负面影响。具体目标1旨在表征酒精喂养对BAT功能的影响，具体目标2旨在提供对该影响的机制见解。具体而言，在具体目标2中，我们将检验酒精诱导的类维生素A代谢失调有助于酒精诱导的BAT生理学改变的假设。这一假设起源于类维生素A对BAT分化和功能的既定影响，以及我们的初步数据，这些数据表明酒精喂养小鼠的BAT改变了组织类维生素A水平，以及类维生素A代谢中重要基因的基因表达水平的变化。我们计划对酒精喂养的小鼠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，其中饮食中的类维生素A含量已经改变。我们希望从这些实验中获得的数据将证实我们的假设，即酒精消费破坏BAT类维生素A稳态，从而影响BAT功能。总之，这项R21申请中提出的研究将探索一个新的概念，即长期饮酒通过对BAT的影响来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械理解。

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.