2007 Annual Report 1a.Objectives (from AD-416) The objective of this cooperative research is to identify a number of genes that affect the expression of childhood obesity in Hispanic children; establish a reference model of body composition in children; understand the barriers and facilitators to the physcial activity guildelines of the 2005 Dietary Guidelines for Americans; determine the contribution of leukocytes to the composition and function of adipose tissue; determine whether a 12-week exercise program without intent to weight loss would increase insulin sensitivity and reduce insulin secretion and glucose production from gluconeogenesis in obese adolescents; and to test the efficacy of an after-school physical activity program that meets the Healthy People 2010 guidelines for lowering body fat, increasing activity energy expenditure and physical activity level in Hispanic children. 1)Genetic and Environmental factors Contributing to Childhood Obesity - Identify a number of genes that affect the expression of childhood obesity in Hispanic children. 2) Biological Diversity of Human Growth: Body Composition Reference Standards for Children - Develop a greater understanding of the changes in body composition starting in infancy, using multiple, independent assays for bone, muscle, water, and body fat content. 3) Barriers and Facilitators to the Physical Activity Guidelines of the 2005 Dietary Guidelines for Americans - identify what environmental and/or personal factors will be necessary for most Americans to adhere to these recommendations. 4) Nutritional Influences on Innate Immunity - Study two aspects of the innate immune system in a mouse model of dietary induced obesity as there is increasing interest in the effects of obesity on components of the innate immune system with regard to its role in host resistance to infection and its capacity to cause tissue injury. 5) Effects of Ethnicity, Exercise and Obesity on Glucose Metabolism and Insulin Sensitivity in Healthy Adolescents - Increase our understanding of the metabolic effects of ethnicity, exercise and obesity in adolescents and possibly identify factors, which may increase the risk of type 2 diabetes and design new treatment strategies to prevent or delay the development of type 2-diabetes in adolescents. 6) Circadian Clocks in Adipose Biology and Obesity - is to maintain a greater understanding that altered sleep patterns associated with our "24-hour" lifestyle may contribute to the accumulation of body fat, and that such altered sleep patterns may ultimately represent alterations in both the central and peripheral circadian clock mechanisms. 1b.Approach (from AD-416) 1) Genetic and Environmental factors Contributing to Childhood Obesity - Perform a genome scan to identify loci that influence quantitative phenotypes related to adiposity, the regulation of food intake, energy expenditure, and energy partitioning in children. Phenotyping of the children will occur which includes anthropometry, body composition, food intake, eating behavior, energy expenditure, fitness, and physical activity, and metabolites, hormones and cytokines involved in energy homeostasis. Weight changes after initial phenotyping and after a weight loss intervention will be measured to determine if weight changes and the metabolic, hormonal and immunologic responses to weight changes are dependent upon genotype. 2) Biological Diversity of Human Growth: Body Composition Reference Standards for Children - Determining the normal biological diversity during growth among different ethnic groups (European-, African-, and Mexican-American). From these data, a multi-level Reference Model of Pediatric Body Composition will be established using LMS statistical modeling techniques. Quantitative indices will be developed to identify infants and young children with abnormal body composition most often associated with increased risk for chronic adulthood diseases. Development of unique and innovative in vivo assays specific to the pediatric population will be established. 3) Barriers and Facilitators to the Physical Activity Guidelines of the 2005 Dietary Guidelines for Americans - implementing an intensive physical activity intervention in African and Mexican American families that will assist in determining specific barriers/facilitators for African and Mexican American children and families adhering to the 2005 physical activity Dietary Guidelines. 4) Nutritional Influences on Innate Immunity - Analyze the accumulation and potential functions of leukocytes in adipose tissue, and the accumulation and capacity for injury of leukocytes in the liver. 5) Effects of Ethnicity, Exercise and Obesity on Glucose Metabolism and Insulin Sensitivity in Healthy Adolescents - Study 96 adolescents on three occasions using state of the art stable isotope and magnetic resonance imaging (MRI) techniques. 6) Circadian Clocks in Adipose Biology and Obesity - employ both hypothesis-generating and hypothesis-testing approaches to ascribe roles for the circadian clock within the adipocyte. 3.Progress Report The ADODR monitors activities for the project through communication with the Center Director, consulation with the On-Site Representative, review of cooperator reports, conference calls, and site visits. 4.Accomplishments Providing Preliminary Results on the Effects of Exercise on Insulin Sensitivity and Fat Distribution in Adolescents: Additional information is needed on the impact of exercise programs for obese adolescents. Children's Nutrition Research Center researchers demonstrated that controlled exercise training without weight loss resulted in increased fitness, reduced visceral fat accumulation in the abdomen and surrounding vital organs, and improved insulin sensitivity in obese adolescents. In addition, in obese adolescents with fatty liver, the exercise program reduced the amount of liver fat substantially (~ 40%). These preliminary results indicate that a moderate exercise program that can be accomplished by sedentary obese adolescents without losing weight can significantly improve their metabolic parameters involved in obesity-related disease. Findings from this study can be used in schools and obesity clinics as a strategy to improve insulin sensitivity and potentially delay or reduce the risk of type 2 diabetes mellitus. [NP107, Component 6 Prevention of Obesity & Disease] (CNRC Project 5) T cell Accumulation in Adipose Tissue: The molecular mechanism responsible for the inflammatory response in diet-induced obesity is not completely understood. Children's Nutrition Research Center researchers documented for the first time that white blood cells accumulated in fat tissue of obese individuals. Additionally, researchers identified a protein that is capable of attracting these cells to fat tissue. Researchers analyzed cell types and proteins in adipose tissue in an animal model (mice fed a diet high in saturated fatty acids) and in human biopsy tissue (humans with morbid obesity and the metabolic syndrome). The outcome of this work will be very important since it is the first step in analyzing the contributions of the immune system in adipose tissue, and it provides another marker for the early detection of systemic inflammation in obesity. [NP107, Component 6 Prevention of Obesity & Disease] (CNRC Project 4) ICAM-1 and Activated Macrophages in Adipose Tissue: Identifying the molecular mechanism responsible for the inflammatory response in diet-induced obesity is needed. Scientists at the Children's Nutrition Research Center documented activated macrophages in fat tissue in diet-induced obesity, and identified an important marker for inflammation in the tissue. TResearchers analyzed adipose tissue and blood in an animal model (mice fed a diet rich in saturated fatty acids). The impact of this work is very significant since it represents the recognition of a second white blood cell type in fat inflammation and the occurrence of a key marker. [NP107, Component 6 Prevention of Obesity & Disease] (CNRC Project 4) Identification of Clock-Regulated Genes within the Adipocyte: Through our experiments, Children's Nutrition Research Center scientists identified the clock-regulated genes within the fat cell. Genes within pathways related to transport, transcription, development, cell cycle, metabolism, cell division, and in particular, lipid biosynthesis were found to be altered in adipocyte-specific dominant negative CLOCK mutant (ACM) mice. Many of these genes were not known to be regulated by the circadian clock (internal body clock) prior to these experiments. Genes related to lipogenesis, or the production of lipids, were all elevated at the transition from sleeping to waking in the transgenic animals, indicating increased potential for fat formation during this time period. These findings suggest that the nutrient makeup of the diet and timing of feeding may both impact and/or be impacted by disruptions in normal patterns of circadian rhythms. [NP107, Component 6 Prevention of Obesity & Disease] (CNRC Project 6) Characterization of an Adipocyte-Specific CLOCK Mutant Animal Model: Scientists at the Children's Nutrition Research Center, Houston, TX ,established a transgenic colony of adipocyte-specific dominant negative CLOCK mutant (ACM) mice. The ACM animal model is the first model with a specific disruption of the circadian clock only within the fat cell. While other animal models with a global loss of the circadian clock have been reported to develop obesity and associated co-morbidities, both behavior and metabolism are altered in these ubiquitously disrupted animals, and it is not known whether the development of obesity in these animals is due to behavioral changes or direct alterations by the circadian clock. Through the use of the ACM animal model, we will be able to understand the means by which alterations in circadian patterns of metabolism and gene expression can lead to obesity. [NP107, Component 6 Prevention of Obesity & Disease] (CNRC Project 6) Assessing DXA Software for Improved Accuracy: In order to accurately calculate body composition measurements in children, additional assessment of the dual energy X-ray absorptiometry (DXA) tool and related software is needed. Our independent assessment of the newest software changes for DXA scans in children have shown that body fat values are increased for all children weighing less than 40 kg, compared with older software once used. Therefore, children examined in 2007 could appear to have increased body fatness compared with children of the same weight from only a few years ago. This software effect may contribute to a false perception that children are continuing to get fatter, which is important to recognize in nutrition-related research. Most importantly, a more accurate tool can be utilized for future research in children. [NP107, Component 6 Prevention of Obesity & Disease] (CNRC Project 2) 6.Technology Transfer