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，和具体的挑战主题：06-DK-102*肥胖是由于能量摄入和能量消耗不平衡造成的。在肥胖患者中，这些多余的卡路里被储存在白色脂肪组织(WAT)中，这些脂肪组织分布在全身的皮下和腹部区域。能量消耗以活动的形式发生，并以维持细胞功能和产生热量或产热的基本热量需求的形式发生。很早就知道，哺乳动物的产热可以通过两个主要来源完成：棕色脂肪组织(BAT)和骨骼肌，前者直接通过产热对基础能量和诱导能量的消耗起重要作用，后者通过颤抖产生热量。棕色脂肪组织特别令人感兴趣，因为最近的研究表明，BAT除了在产生热量方面发挥作用外，还可能在防止啮齿类动物和人类体重增加和胰岛素抵抗方面发挥作用。的确，因为它的新陈代谢活性非常高。此外，很少有功能性蝙蝠能对新陈代谢产生深远的影响。尽管蝙蝠终生存在于啮齿动物体内，但直到最近，蝙蝠还被认为在成年人类中是不存在的，而且与新陈代谢无关。这是因为，尽管蝙蝠有潜在的生理影响，但一直没有方法来定位和量化蝙蝠的质量，并测量其活动或对刺激的反应。然而，根据我们和其他人最新报道的发现，我们现在知道BAT存在于大多数成年人中；它具有功能活性，可以被生理激活剂刺激；使用18F-氟代脱氧葡萄糖(FDG)PET/CT成像可以识别和量化BAT的质量和活性。PET/CT可以用来识别BAT，这一发现为我们加深对新陈代谢和生热机制的了解开辟了新的领域，然而，在改进这一成像模式以量化人体器官特定能量的产生、利用和热产生方面，仍有许多工作要做。因此，第一组研究(目标1)旨在为我们提供更深入的了解蝙蝠在啮齿动物和人类中的代谢活动。全身能量消耗和体温的补充测量将被测量，并与通过PET/CT进行非侵入性成像的结果相关联。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学研究结合起来，以便我们第一次全面了解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，需要电离辐射，这使得它不适合常规使用和系列研究。因此，我们需要开发替代的、非电离的策略来测量蝙蝠的质量和功能。在目标2中，我们将确定功能磁共振可以作为一种非电离的、更安全的方法来重复测量BAT代谢活动。拟议的研究将为更大规模的努力奠定基础，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蝙蝠的存在和活动。然后，我们将能够测试与蝙蝠质量、功能和激活相关的多种假说，以确定治疗肥胖症和糖尿病的新方法。 与公共健康相关：肥胖，即积累过多的白色脂肪，会增加心脏病发作、糖尿病和包括癌症在内的许多其他疾病的风险。最近的研究表明，成年人有第二种脂肪，称为棕色脂肪，它会燃烧能量，而不是储存能量。我们的研究将开发测量棕色脂肪数量和活性的工具。这是开发刺激棕色脂肪的新方法的第一步，以帮助肥胖者减肥并改善他们的整体健康。

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.