Alcohol Consumption and Brown Adipose Tissue

描述(申请人提供)：这一探索性项目将测试长期饮酒损害棕色脂肪组织(BAT)产热能力的假设，以及这种损害与酒精对BAT类视黄醇代谢的影响有关。该项目有两个具体目标，第一个目标是评估与长期饮酒有关的BAT功能损害，第二个目标将提供对酒精在该组织中的影响的机械性洞察。本项目的研究结果将对酒精中毒、蝙蝠生理学和维甲酸动态平衡的研究具有广泛的意义。蝙蝠在成年人类身上具有生理功能的概念代表了蝙蝠研究领域的一种范式转变，并导致人们对这种迄今未被重视的组织产生了越来越大的兴趣。我们的初步数据显示，长期饮酒与体温维持的失调以及蝙蝠体重的显著减少有关。在具体目标1中，将系统地研究长期饮酒对蝙蝠产热的功能后果。通过一系列的酒精饲养研究，我们将评估酒精饲养对蝙蝠形态和机能的影响。酒精喂养的小鼠的产热能力将使用两种成熟的技术进行测试：对寒冷暴露的反应性和对去甲肾上腺素挑战的反应性。我们希望确定长期饮酒对成年小鼠的BAT产热能力有负面影响。虽然特定目标1旨在描述酒精喂养对蝙蝠功能的影响，但特定目标2旨在提供对这种影响的机械性洞察。具体地说，在特定的目标2中，我们将检验酒精诱导的视黄醇代谢失调导致酒精诱导的蝙蝠生理变化的假设。这一假说起源于维甲酸对蝙蝠分化和功能的既定影响，以及我们的初步数据表明，酒精喂养的小鼠的蝙蝠改变了组织中的维甲酸水平，以及在维甲酸代谢中重要的基因表达水平的变化。我们计划对酒精喂养的小鼠的BAT中的维甲酸代谢进行全面的分析；我们还将进行酒精喂养实验，其中饮食中的维甲酸含量发生了变化。我们预计，从这些实验中获得的数据将证实我们的假设，即酒精消费破坏了蝙蝠类维甲酸的动态平衡，从而影响了蝙蝠的功能。总而言之，这项R21应用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。关于这些创新假说产生的数据将影响有关饮酒对肝脏以外的组织(特别是BAT)的影响的一般概念，并提供对这些变化的机械性理解。

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.