Imaging Strategies to Measure Brown Fat and Its Activity

描述（由申请人提供）：本申请涉及广泛的挑战领域（06），使能技术和特定挑战主题：06- dk -102*肥胖是由能量摄入和能量消耗之间的不平衡引起的。在肥胖中，这些多余的卡路里被储存在白色脂肪组织（WAT）仓库中，分布在全身的皮下和腹腔区域。能量消耗以活动的形式发生，以维持细胞功能和产生热量或产热的基础热量需求的形式发生。人们早就知道，在哺乳动物中，产热可以通过两个主要来源来完成：棕色脂肪组织（BAT）和骨骼肌，前者对直接通过产热产生的基础和诱导能量消耗都很重要，后者通过颤抖产生热量。棕色脂肪组织受到特别关注，因为最近的研究表明，除了在产生热量方面的作用外，BAT还可能在防止啮齿动物和人类体重增加和胰岛素抵抗方面发挥作用。确实，因为它的代谢活性非常高。此外，很少的功能性BAT可以产生深远的代谢影响。尽管BAT在啮齿类动物的一生中都存在，但直到最近，人们才认为BAT不存在，并且与成年人的代谢无关。这是因为，尽管有潜在的生理影响，但没有方法来定位和量化BAT的质量，并测量其活性或对刺激的反应。然而，根据我们和其他人最新报告的发现，我们现在知道BAT存在于大多数成年人中；它具有功能活性，可以受到生理激活剂的刺激；使用18f -氟脱氧葡萄糖（FDG） PET/CT成像可以确定和量化BAT的质量和活性。PET/CT可用于识别BAT，这一发现为我们对新陈代谢和产热的理解开辟了新的领域，然而，在完善这种成像方式以量化人体受试者的器官比能产生、利用和产热方面仍需要做大量工作。因此，第一组研究（Aim 1）旨在让我们对啮齿动物和人类的BAT代谢活性有更深入的了解。将测量全身能量消耗和温度的补充测量，并与PET/CT无创成像结果相关联。我们将把这些全身测量与组织、细胞和基因表达水平的生理研究结合起来，这样我们将首次全面了解BAT是如何发挥作用并对新陈代谢产生有益影响的。然而，PET/CT价格昂贵且需要电离辐射，因此不适合常规使用和系列研究。因此，我们需要开发替代的非电离策略来测量BAT的质量和功能。在Aim 2中，我们将确定功能性MRI可以作为一种非电离的、更安全的方法来重复测量BAT代谢活性。拟议的研究将为更大的努力奠定基础，旨在开发一个研究平台，利用啮齿动物和人类的全身成像和代谢分析来评估BAT的存在和活性。然后，我们将能够测试与BAT质量、功能和激活相关的多种假设，以确定治疗肥胖和糖尿病的新方法。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06), Enabling Technologies, and Specific Challenge Topic: 06-DK-102* Obesity results from an imbalance between energy intake and energy expenditure. In obesity these excess calories are stored in white adipose tissue (WAT) depots that are distributed throughout the body in both subcutaneous and intra-abdominal areas. Energy expenditure occurs in the form of activity and in basal caloric needs for maintenance of cell function and for generating heat, or thermogenesis. It has long been known that in mammals, thermogenesis can be accomplished through two primary sources: brown adipose tissue (BAT), which is important for both basal and inducible energy expenditure directly via thermogenesis, and skeletal muscle, which generates heat through shivering. Brown adipose tissue is of particular interest since recent studies suggest that in addition to its role in heat generation, BAT may also play a role in protection from weight gain and insulin resistance in both rodents and humans. Indeed, because of its very high metabolic activity. Furthermore, very little functional BAT can have a profound metabolic impact. Although BAT is present in rodents throughout life, until recently BAT was thought to be nonexistent and metabolically irrelevant in adult humans. This was due to the fact that, despite its potential physiological impact, there had been no methods to localize and quantify BAT mass and measure its activity or response to stimulation. However, based on newly reported findings by us and others, we now know that BAT is present in most adult humans; it is functionally active and can be stimulated by physiological activators; and that BAT mass and activity can be identified and quantified both in mass and activity using 18F-fluorodeoxyglucose (FDG) PET/CT imaging. The observation that PET/CT can be used to identify BAT now opens the field to increase our understanding metabolism and thermogenesis, however, much work is still needed in refining this imaging modality to quantify organ specific energy production, utilization, and heat production in human subjects. Therefore, the first set of studies (Aim 1) is designed to provide us with a much deeper understanding of BAT metabolic activity in both rodents and humans. Complementary measures of whole-body energy expenditure and temperature will be measured and correlated with findings using noninvasive imaging via PET/CT. We will combine these whole-body measures with physiological studies at the levels of the tissue, cell, and gene expression so that we will have for the first time a full picture of how BAT functions and exerts its beneficial effects on metabolism. However, PET/CT is expensive and requires ionizing radiation, making it unappealing for routine use and serial studies. We therefore need to develop alternative, nonionizing strategies to measure BAT mass and function. In Aim 2, we will determine functional MRI can be used as a nonionizing, safer way to do repeated measurements of BAT metabolic activity. The proposed studies will set the stage for larger effort designed to develop a research platform utilizing whole-body imaging and metabolic assays in both rodents and humans to evaluate the presence and activity of BAT. We will then be able to test multiple hypotheses related to BAT mass, function, and activation, to identify novel methods to treat obesity and diabetes. PUBLIC HEALTH RELEVANCE: Obesity, i.e. accumulation of excess white fat, increases the risk for heart attacks, diabetes and many other diseases, including cancer. Recent studies show that adults have a second type of fat called brown fat, which burns energy instead of storing it. Our research will develop the tools to measure the amount and activity of brown fat. This is the first step toward developing new ways to stimulate brown fat to help obese people lose weight and improve their overall health.