The prevalence of overweight and obesity in children and adults has doubled during the past 20 years. The alarming rise in body weight has likely occurred because the current environment affords easy access to calorie-dense foods and requires less voluntary energy expenditure. However, such an environment leads to obesity only in those individuals whose body weight regulatory systems are not able to control body adiposity with sufficient precision in our high-calorie/low-activity environment, which suggests that some subgroups in the United States have a uniquely high susceptibility to weight gain under the prevailing environmental conditions. Our research is directed at increasing our understanding of the metabolic and behavioral factors involved in determining body weight regulation and body composition during childhood, with a special emphasis on minority populations. Our ongoing research program prospectively evaluates risk factors for the development of obesity and its complications in children, studies the effects of anorectic medications on body weight and obesity-related comorbid conditions in children, and seeks the genetic and environmental factors important for the markedly greater incidence of obesity and its comorbid conditions in some U.S. minority populations. A second research direction examines the pathophysiology of HIV-associated lipodystrophy in children and adults.

Molecular Studies of Childhood Body Weight Regulation
Feng, Adler-Wailes, Elberg, Carr, Liu, Yanovski J; in collaboration with Warden
Using classical association studies, we are studying polymorphisms in genes involved in the leptin signalling pathway and thus are attempting to identify gene variants with an impact on body composition that differ in frequency between African American and Caucasian children. Genes currently under study include proopio-melanocortin (POMC), POMC processing enzymes, the melanocortin receptors 3, 4, and 5, and neuropeptide Y and its receptors. In addition, we have studied genes important for energy expenditure, such as the mitochondrial uncoupling proteins, and genes potentially involved in cortisol metabolism that may influence intra-abdominal adipose tissue, such as 11-beta-hydroxysteroid dehydrogenase. We have found that a 45 base-pair insertion polymorphism in the eighth exon of UCP-2 is associated with excess body weight in African American, Asian, and Caucasian children. We have also identified novel polymorphisms in the POMC sequence that are more prevalent in African American than Caucasian children but do not appear to play a role in the greater body adiposity of African American children. A polymorphism in the melanocortin 3 receptor that is associated with adiposity in a large cohort of children appears to have functional significance for signal transduction. Ongoing studies attempt to understand the mechanisms by which these sequences alterations may affect body weight.

Physiology, Metabolism, and Psychology of Childhood Body Weight Regulation
Uwaifo, McDuffie, Bonat, Parikh, Elberg, Fallon, Nguyen, Morgan, Tanofsky-Kraff, Yanovski J; in collaboration with Young-Hyman, Schoeller, Warden, Yanovski S, Keil
Given that the amount of visceral fat in Caucasians is highly associated with the complications of obesity, we have studied the distribution of adipose tissue in African American and Caucasian children along with methods for assessing children’s insulin resistance and body composition. We have found less visceral abdominal adipose tissue in non-obese and obese African American children than in Caucasian children but considerably greater insulin resistance in African American children. In recent studies, the hyperglycemic clamp procedure in children was highly correlated with the more technically demanding euglycemic, hyperinsulinemic clamp study and proved suitable for assessing children’s insulin sensitivity. African American children were then found to have greater insulin secretion, a greater prevalence of acanthosis nigricans, and less insulin sensitivity than Caucasian children of similar body composition. The results imply that the relationship between visceral fat and the complications of obesity may be different in African Americans and Caucasians. The susceptibility to weight gain in African American children may also result from differences in metabolic efficiency. We have also found that resting energy expenditure is approximately 90 kcal/d less in African American than in Caucasian normal-weight and overweight boys and girls. Our studies suggest that the differences are not explained by differences in the hormone leptin. We have also studied the effects of adiposity on skeletal maturation in African American and Caucasian children, finding that a substantial portion of the advancement of sexual and skeletal maturation found in African American children may be explained by their greater adiposity.

In two ongoing protocols (83-CH-0169 and 96-CH-0101) designed to determine the factors that are most important for development of the complications of obesity in African American and Caucasian youth, we are studying normal-weight African American and Caucasian children and adolescents, already obese African American and Caucasian children, and the non-obese African American and Caucasian children of obese parents. We are examining body composition, metabolic rate, insulin sensitivity, glucose disposal, and genetic factors believed to regulate metabolic rate such as the uncoupling proteins, leptin and its receptor, and the beta-3 adrenergic receptor. We are also studying psychological and behavioral factors, such as propensity to engage in binge eating behavior. We have recently found that children who report binge eating episodes during childhood have greater adiposity than those not reporting such episodes. Children are being studied longitu-dinally into adulthood. We hypothesize that differences in various factors will predict the development of obesity in the populations studied and may be of great importance in developing rational approaches for the prevention and treatment of obesity in the diverse U.S. population.

Treatment of Children and Adolescents with Comorbid Conditions Associated with Obesity
Uwaifo, McDuffie, Bonat, Parikh, Fallon, Elberg, Chin, Tanofsky-Kraff, Yanovski J; in collaboration with Drinkard, Sebring, Salaita, Riggs, Young-Hyman, Calis, Reynolds, Krakoff, Rolls
Given the rapid increase in the prevalence of obesity, the development of treatments for obesity in childhood is urgently needed. In two ongoing clinical protocols, we are studying novel approaches for controlling body weight in children. We have completed a pilot study demonstrating that severely overweight adolescents can lose weight when enrolled in a comprehensive weight management program that includes the novel gastrointestinal lipase inhibitor orlistat as an adjunct to a behavioral modification program. We have also found evidence that one mechanism through which orlistat may affect body weight is by changing the hedonic value of dietary fat. A placebo-controlled randomized trial will determine whether the use of orlistat improves the weight loss of African American and Caucasian children and adolescents with obesity-related comorbidi-ties. A second study examines the mechanism by which another novel weight loss agent, metformin, may affect the body weight of younger children with hyperinsulinemia.

Etiology of HIV-Associated Lipodystrophy
Adler-Wailes, Feng, Yanovski J
We are actively engaged in understanding the syndrome of HIV-associated lipodystrophy. Since it was initially recognized in 1982, acquired immunodeficiency syndrome (AIDS) has been a leading cause of death among children and young adults in the U.S. for much of the last decade. Following the introduction of protease inhibitors as part of “highly active antiretroviral therapy” (HAART) for the treatment of HIV- infected patients, AIDS-related morbidity and mortality decreased dramatically. However, HIV-infected children and adults, particularly those treated with protease inhibitors, often develop a lipodystrophy that includes significant changes in body shape, with fat loss in the face, arms, and legs and fat gain in the trunk. This lipodystrophy is often accompanied by hypertriglyceridemia, hypercholesterolemia, and hyperinsulinemia. Understanding the patho-physiology of lipodystrophy is therefore important for the long-term therapy of HIV infection. In addition, given that certain types of body habitus are associated with increased risks of cardiovascular disease in non–HIV-infected individuals, an enhanced understanding of the control of adipocyte physiology and fat distribution may have additional significance for the broader population. We have studied the etiology of HIV-associated lipodystrophy in clinical populations; we reported an increase in visceral adipose tissue in HIV-infected adults, found marked abnormalities in both insulin sensitivity and control of cholesterol and triglyceride metabolism, and examined the metabolic consequences of interrupting HAART. Subsequent studies have ruled out alterations in the hypothalamic-pituitary-adrenal axis as causes of this syndrome. In our ongoing studies, we are attempting to elucidate the alterations in adipocyte function that arise as a result of exposure to the components of HAART. Preliminary analyses suggest that the protease inhibitor ritonavir significantly affects hormone-stimulated lipolysis as well as transcription of numerous adipocyte-specific and non–adipocyte-specific genes.

Environmental Factors Affecting Adult Weight Gain
Parikh, Nguyen, Sovik, Chin, Yanovski J; in collaboration with Yanovski S
We are also interested in assessing the impact of the environment on body weight gain. To determine the role of seasonal variation in weight change, we prospectively studied 200 U.S. adults, following them longitudinally. We found that the only time period during which weight changes significantly is during the fall-winter holiday season between Thanksgiving and New Year’s Day. Such studies have implications for individuals attempting to control their weight. We are also interested in the role dietary calcium plays in determining body weight change. A new protocol attempts to examine the impact of dietary calcium supplementation on body weight in a randomized, controlled trial of 340 adults.