Imaging Strategies to Measure Brown Fat and Its Activity

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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.