The prevalence of overweight in children, adolescents, 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, the current 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, suggesting that subgroups in the United States share a uniquely high susceptibility to weight gain under the prevailing environmental conditions. Indeed, certain ethnic and racial subgroups do appear to have more difficulty matching caloric intake and energy output in this environment, predisposing them to a greater incidence of overweight and obesity. One such group is African Americans. During adolescence, African American boys and girls experience a steady rise in BMI such that over 18 percent of African American girls (versus about 8 percent of Caucasian girls) and about 10 percent of African American boys (versus about 6 percent of Caucasian boys) have a BMI in the 95th percentile or higher. Socioeconomic or cultural factors do not fully account for these differences in prevalence. The greater adiposity of African American children and adolescents confers risks for obesity’s comorbid conditions, such as Type 2 diabetes, hypertension, and atherosclerotic cardiovascular disease. These obesity-related comorbid conditions contribute to the greater mortality among some ethnic groups in the United States. However, data also suggest that the predictive risk factors related to body composition and the therapeutic approaches for comorbid conditions that are derived from the study of Caucasians may be less applicable to those of different ethnicity or race. Effective prevention and treatment of obesity-related disorders requires a better understanding of the key elements for body weight regulation.

The research of the Unit on Growth and Obesity (UGO) 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. The ongoing research program prospectively evaluates risk factors for the development of obesity and its complications in children and adolescents, studies the effects of the new weight loss medications on body weight and obesity-related comorbid conditions in children and adolescents, and seeks to identify 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 line of research examines the pathophysiology of HIV-associated lipodystrophy in children and adults.

Molecular Analysis of Childhood Body Weight Regulation
Feng, Adler-Wailes, Yanovski
Using classical association studies, we are studying polymorphisms in genes involved in the leptin signaling pathway, thereby attempting to identify gene variants influencing body composition, variants whose frequency differs between African American and Caucasian children. Genes currently under study include proopiomelanocortin, 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. 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.

Physiology, Metabolism, and Psychology of Childhood Body Weight Regulation
Uwaifo, McDuffie, Bonat, Parikh, Nguyen, Sovik, Nicholson, Tanofsky-Kraff, Yanovski
Because 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. We have found that there is less visceral abdominal adipose tissue (fat deposited around the abdominal organs) in nonobese and obese African American children than in Caucasian children, but considerably greater insulin resistance in African American children. The results imply that the relationship between visceral fat and the complications of obesity differs in African Americans and Caucasians. The susceptibility to weight gain in African Americans 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.
In two ongoing protocols, we are studying normal-weight African American and Caucasian children and adolescents, African American and Caucasian children who are already obese, and the nonobese African American and Caucasian children of obese parents in order to determine if racial differences in body composition, metabolic rate, insulin sensitivity, glucose disposal, or genetic factors believed to regulate metabolic rate, such as the uncoupling proteins, leptin and its receptor, and the beta-3 adrenergic receptor exist before puberty. Psychological and behavioral factors, such as propensity to engage in binge eating, are also under investigation. Children are being studied longitudinally into adulthood. We hypothesize that differences in these factors will predict the development of obesity in the subject populations 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, Nicholson, Yanovski
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 to the control of 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 comorbidities. A second study examines the mechanism by which another novel weight loss agent, Metformin, may affect the body weight of younger children with hyperinsulinemia.

Importance of Subcutaneous versus Visceral Adipose Tissue in the Comorbid Conditions Associated with Obesity
Yanovski, Uwaifo
The risks of obesity-related comorbid conditions, such as hypertension, dyslipidemia, diabetes, and atherosclerotic heart disease, rise as the amount of visceral adipose tissue increases. However, it is unknown to what extent the complications of obesity are attributable to the metabolic actions of visceral adipose tissue or to those of subcutaneous adipose tissue throughout the body. Some have posited that visceral adipose tissue, of which subcutaneous abdominal adipose tissue is the most important, is one of many markers for the metabolic conditions that cause comorbid conditions in humans. To study this question, we have examined the metabolic consequences of the removal of large quantities of subcutaneous adipose tissue by large volume liposuction (LVL). Our preliminary data suggest that fasting insulin concentrations and blood pressure decrease substantially after large quantities of subcutaneous adipose tissue are removed by LVL. Ongoing studies will replicate this phenomenon and study the underlying mechanisms.

Etiology of HIV-Associated Lipodystrophy
Yanovski, Adler-Wailes
The UGO is studying the syndrome of HIV-associated lipodystrophy. Following its initial recognition in 1982, acquired immunodeficiency syndrome (AIDS) was a leading cause of death among children and young adults in the United States for much of the last decade. With, however, 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. Nonetheless, 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. The lipodystrophy is often accompanied by hypertriglyceridemia, hypercholesterolemia, and hyperinsulinemia. Understanding the pathophysiology of lipodystrophy is therefore important for the long-term therapy of HIV infection. In addition, since 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 that visceral adipose tissue increases in HIV-infected adults as do abnormalities in both insulin sensitivity and control of cholesterol and triglyceride metabolism. Accordingly, we have examined the metabolic consequences of interrupting HAART. Subsequent studies have ruled out alterations in the hypothalamic-pituitary-adrenal axis as causative in lipodystrophy. Ongoing studies are attempting to elucidate the alterations in adipocyte function that arise as a result of exposure to the components of HAART.