Molecular, Cellular, and Genetic Characterization of Human Adipose Tissue and Its Role in Metabolism

More than ever before, people are eating more calories from food than what they are burning off through exercise and other activities, and this imbalance is causing the rising rates of obesity and diabetes in the US and throughout the world. The different types of body fat are central players in this process. The white fat stores excess calories coming from food, while brown fat - also known as brown adipose tissue, or BAT - consumes the energy from food to generate heat. This important process in BAT is achieved through the action of a special protein found only in BAT, called uncoupling protein 1 (UCP1). Scientists used to believe that BAT was important only in small animals and human infants, but it was recently discovered by us and others that in response to mild cold exposure, adult human BAT (hBAT) consumes more glucose by weight than any other tissue. In addition, human BAT may also combat weight gain by becoming more active in the setting of increased food consumption. This phenomenon has already been demonstrated in mice and rats, and its presence suggests that activation of human BAT could be used as a safe treatment for obesity and metabolic disease. Finally, emerging evidence indicates that human BAT may be an endocrine organ, which means that it releases hormones into the blood and regulates other organs of the body as well, including skeletal muscle, liver, and the insulin-releasing pancreatic Beta-cell. If we are going to understand how hBAT functions in the body physiology and use its calorie-burning ability to treat illnesses of metabolism such as diabetes, we will need to approach the challenge using several different methods. One key reason is that BAT is not easy to find in the body, and the cells that make it up are different depending on where they are and what the body needs. Brown fat is composed of at least two known types of distinct cells, termed "constitutive"/brown and "inducible"/beige; and there are also white fat cells in varying proportions. Given that there is currently no known way to estimate the amount of brown fat in the body from a simple blood test, our lab group has successfully relied on collecting small amounts of fat from the site of surgery in patients who are already undergoing clinically indicated procedures. Information obtained from these fat tissues has addressed questions related to (a) how brown fat cells develop from immature stem cells; (b) what genes are active; and (c) how many calories the brown fat can burn. These earlier studies have also provided the preliminary cells necessary for establishing long-lasting human brown and white cells that can be grown indefinitely in the laboratory. Despite this progress, much remains unknown about the functional differences between brown and beige fat cells and how these could affect metabolism in humans of different age, sex, and genetic backgrounds, as well as the changes seen in the brown fat cells in different illnesses. The goal of this study is to address these and related questions.