2004 Annual Report 1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? What does it matter? The prevalence of adult and childhood obesity continues to increase in the United States among all ethnic populations. Understanding the factors that contribute to obesity may allow early screening of individuals at increased risk during childhood. Identification of the relevant genes and how their effects are mediated by the environment, and by growth and development, will provide a basis to develop preventative, nutritional, and therapeutic interventions. To better define the frequency of obesity in children, we have established the range of normal body composition (bone, muscle, water, fat) from birth through adolescents for Caucasian, African-American, and Hispanic-American children. In parallel with the human studies, gene interaction studies in mice have been implemented. We have found that adipose tissue contains a significant number of leukocytes, specifically macrophages and lymphocytes, and that the prevalence of macrophages is significantly greater in female mice. The occurrence of macrophages in adipose tissue has recently been reported in humans, and there is considerable interest in the possible interplay between these cells, which can produce cytokines that alter lipid metabolism, and the adipocytes, which can produce chemokines and cytokines that can alter the functions of macrophages. Given the observations from a number of laboratories that in obesity there are systemic elevations of inflammatory markers, and given the fact that macrophages are known to be a source of many of the commonly identified markers of inflammation, we are interested in defining the extent to which the inflammatory condition found in many obese individuals (as a component of the metabolic syndrome) is linked directly to the interplay of leukocytes and adipocytes in adipose tissue. An extension of this problem deals with the association of the metabolic syndrome with liver injury, and the role of macrophages in the liver is of pathogenic significance. The approach to understanding the interactions between white blood cells, liver cells and adipocytes involve gene profiling and targeted mutations. It is estimated that at least one third of the adult population in the United States is obese. Childhood obesity in the United States also has dramatically increased in the past decade. At the end of the 1980s, at least 1 in 5 children (more than 22%) had excess weight for height, and about half of these children could be classified as obese (above the 95th percentile for the general population). The rate of childhood obesity observed in the United States today is at least double that of the early 1970s. During this 30-year period, the availability of energy-dense foods has increased, while sedentary lifestyles have become more prevalent, and both changes are seen at younger ages. Childhood obesity not only has immediate psychosocial consequences for the child, but also contributes to serious medical complications including hyperinsulinemia, glucose intolerance, and alterations in lipoprotein metabolism. Childhood predisposition to obesity often continues into adolescence, and then into adulthood. The older the overweight or obese child is, the more difficult it is to reverse the condition. Dieting alone has had poor success for the long-term control of obesity at any age. Consequently, knowledge of the metabolic and endocrine consequences of gene responses and interactions at early ages is needed to rationally propose changes in treatment or prevention. There is also increasing evidence that bone formation and mineralization may be altered during childhood obesity, which may contribute to increased prevalence of joint diseases as obese adults. The research to be undertaken is consistent with National Program #107 - Human Nutrition. The human studies component of this project directly relate to the nutrient requirements of children for optimal health. The animal studies relate to the mechanism of gene interactions related to adiposity development and control. 2.List the milestones (indicators of progress) from your Project Plan. Year 1 (2005): Enroll and phenotype 75 families (250 children, 150 adults) Genotype 400 individuals Repeat anthropometry and body composition measurements on 250 children Data entry and error checking Genotyping complete on first and second cohorts (760 individuals) Preliminary QTL linkage analysis Recruitment for Cross-Sectional Pediatric Database Testing of different mathematical models as they relate to the Pediatric Reference Model Statistical analysis of percentile distribution models Extension of BodPod assay to include preschool ages and testing of PedPod instrument for infants Year 2 (2006): Enroll and phenotype 75 families (250 children, 150 adults) Genotype 400 individuals Repeat anthropometry and body composition measurements on 250 children Data entry and error checking Genotyping complete on third and fourth cohorts (780 individuals) QTL linkage analysis Continue longitudinal recruitment for longitudinal databases Test prediction models with pediatric populations with known abnormal body composition Year 3 (2007): Repeat anthropometry and body composition measurements on 250 children Begin 1-y intervention trial (75 families) Data entry and error checking Fine mapping and sequence positional candidates genes to identify SNPs Improvement of precision and accuracy of DXA software for use with infants and toddlers Continue longitudinal recruitment Identification of growth model that best describes changes in body composition Year 4 (2008): Begin 1-y intervention trial (75 families) Repeat anthropometry and body composition measurements on 250 children Data entry and error checking Fine mapping and sequence positional candidates genes to identify SNPs Continue longitudinal recruitment Test of predictive accuracy of model in longitudinal population Test accuracy of forward prediction of Z-model with longitudinal database and disease populations Development of magnetic resonance technique for body water assay in preterm infants Year 5 (2009): Repeat anthropometry and body composition measurements on 250 children Data entry and error checking QTN analysis Continue longitudinal recruitment Adjust mathematical parameters in model Update CNRC websit with latest Z-score prediction models Development of body nitrogen assay with very loss dose Development of fat distribution assay for use with children 3.Milestones: A. List the milestones that were scheduled to be addressed in FY 2004. How many milestones did you fully or substantially meet in FY 2004 and indicate which ones were not fully or substantially met. This research project has recently received peer review certification; therefore no milestones were reached during the reporting year. B. List the milestones that you expect to address over the next 3 years. What do you expect to accomplish, year by year, over the next 3 years under each milestone? Year 1 (2005): Enroll and phenotype 75 families (250 children, 150 adults) -Initiate enrollment and collect physical data Genotype 400 individual -Analyze and collect genetic data Repeat anthropometry and body composition measurements on 250 children -Conduct DXA analysis Data entry and error checking -Compute and monitor variable to minimize the degree of error Genotyping complete on first and second cohorts (760 individuals) -Complete genotypic analysis Preliminary QTL linkage analysis -Analyze QTL linkage to determine possible covariants Recruitment for Cross-Sectional Pediatric Database -Initiate recruitment Testing of different mathematical models as they relate to the Pediatric Reference Model -Evaluate mathematical computations to determine mechanisms and accuracies of the existing models Statistical analysis of percentile distribution models -Develop understanding of key models Extension of BodPod assay to include preschool ages and testing of PedPod instrument for infants -Commence measurements for youth in utilizing scientific tools Year 2 (2006): Enroll and phenotype 75 families (250 children, 150 adults) -Initiate enrollment and collect physical data Genotype 400 individual -Analyze and collect genetic data Repeat anthropometry and body composition measurements on 250 children -Conduct DXA analysis Data entry and error checking -Compute and monitor variable to minimize the degree of error Genotyping complete on third and fourth cohorts (780 individuals) -Complete genotypic analysis of third and fourth groups QTL linkage analysis -Analyze QTL linkage to determine possible covariants Continue longitudinal recruitment for longitudinal databases -Continue recruitment for data collection Test prediction models with pediatric populations with known abnormal body composition -Measure key subjects to develop constants Year 3 (2007): Repeat anthropometry and body composition measurements on 250 children -Conduct DXA analysis Begin 1-y intervention trial (75 families) -Initiate trial studies Data entry and error checking -Compute and monitor variable to minimize the degree of error Fine mapping and sequence positional candidates genes to identify SNPs -Scientific analysis to mark SNPs Improvement of precision and accuracy of DXA software for use with infants and toddlers -Enhance software for less variance Continue longitudinal recruitment -Continue recruitment for data collection Identification of growth model that best describes changes in body composition -Define model to meet developmental stages 4.What were the most significant accomplishments this past year? A. What were the most significant accomplishments during FY2004: None. Accomplishments for FY 2004 may be viewed on 6250-51000-037-00D. B. Other significant accomplishments, if any: None. Accomplishments for FY 2004 may be viewed on 6250-51000-037-00D. C. Significant activities that support special target populations: None. 5.Describe the major accomplishments over the life of the project, including their predicted or actual impact. To provide a sense of history and continuity that ties this research project with that of the previous project, please refer to project (250-51000-037-00D for past accomplishments. 6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? None. 7.List your most important publications in the popular press and presentations to organizations and articles written about your work. None. Publications for FY 2004, may be viewed on 6250-51000-037-00D