Project Number: 6250-51000-046-00
Project Type: Appropriated

Start Date: May 21, 2004
End Date: Apr 30, 2009

Objective:
1) Identify a number of genes that affect the expression of childhood obesity in Hispanic children, investigate strong positional candidate obesity-related genes, and test if weight changes and metabolic, hormonal and immunologic responses to weight changes are dependent upon genotype; 2) Establish a reference model of body composition in children; 3) Identify barriers and facilitators for the physical activity component of the 2005 Dietary Guidelines for Americans and relate to obesity risk in urban, African-and Mexican-American children and families; 4) Determine the contribution of leukocytes to the composition and function of adipose tissue, investigate the influence of dietary factors on the composition of leukocytes within adipose tissue and liver, and explore how obesity can both reduce host resistance and enhance inflammatory tissue injury; 5) To 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 if so, whether these changes are associated with a decrease in intramyocellular and intrahepatic fat content; and 6) To develop 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.

Approach:
1) A systemic genomic scan and follow-up fine mapping and sequencing of positional candidate genes will be performed on 300 overweight Hispanic children and their biological parents and siblings with respect to adiposity, the regulation of food intake, energy expenditure and energy partitioning before and after weight loss. 2) A 5-level body composition model will be determined from multiple-method body composition assessments in 1500 multi-ethnic children. The predictive accuracy of the model for the individual will be verified by longitudinal restudy. 3) Implement an intensive physical activity intervention in urban African- and Mexican-American families that will assist in determining specific barriers/facilitators for children and families adhering to the physical activity component of the 2005 Dietary Guidelines. 4) Animal models (murine) and human tissue will be used to characterize myeloid and lymphoid cells within adipose tissue and changes that occur in mice fed high fat diets. Phenotypic markers and in situ hybridization will be used to characterize the cell types, ultrastructural studies, and confocal microscopy will define the position of these cells in relationship to other structural components of the adipose tissue, and tissue fractionation techniques will be used to isolate these cells for function studies in vitro. Cell lines (e.g., RAW cells and 3T3 cells) will be used to study cytokine, chemokine and hormone release, adipocyte differentiation and lipid metabolism. Contributions of the immune cells to lipid metabolism in vivo will be sought in mice with disrupted or activated (e.g., with endotoxin) immune cell functions. 5) Insulin sensitivity and secretion will be studied using stable isotopes, and intramyocellular and intrahepatic fat content will be determined using MRI. 6) Through employing both hypothesis-generating and hypothesis-testing approaches to ascribe roles for the circadian clock within the adipocyte will increase our understanding of altered sleep patterns and how they may contribute to the accumulation of body fat.