MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN
Project Number: 6250-51000-055-00
Start Date: Mar 31, 2009
End Date: Mar 30, 2014
1) determine role of circadian clock in regulation of food intake and interaction between diet composition and circadian rhythms of food intake on body weight control during post-weaning and adult life; determine specific role of central and peripheral clocks, as well as circadian output pathways in maintaining homeostasis of food intake; (2-3 removed; SYs left); 4) investigate impact of prematurity on GI and metabolic response to perinatal nutrition; 5) compare impact of continuous vs. intermittent bolus delivery of nutrients provided enterally or parenterally on protein synthesis and accretion in neonatal models and identify intracellular signaling mechanism involved; 8) investigate changes of SIRT3 gene expression in the liver, and study effects of SIRT3 expression on hepatic metabolism, oxidative stress, and fat deposition; 9) determine role of protein kinase C interacting cousin of thioredoxin in insulin-mediated growth, macronutrient metabolism, and insulin resistance in the liver; 10) define action of glucagon-like peptide-2 (GLP-2) receptor on food intake and inter-organ macronutrient flux; 11) study ghrelin peptide expression profile under different diet regimes; 12) conduct mechanistic analyses of differences in metabolic profile between WT and null mice; 13) confirm predicted lipotropic effects of lecithin, choline and betaine in high-fat-fed mouse models of the metabolic syndrome; 14) test impact of liver specific LRH-1 knockout on the lipotropic effects of lecithin, choline and betaine in high-fat-fed mouse models of the metabolic syndrome; 15)identify genes that show epigenetic dysregulation in obesity; 16) determine if methylation and expression of specific genes in hypothalamus and/or adipose tissue differ between lean and obese animals and determine if maternal obesity and/or nutrition before and during pregnancy persistently alters epigenetic regulation in offspring; 17) determine if maternal obesity and/or nutrition before and during pregnancy persistently alters epigenetic regulation in offspring hypothalamus or adipose tissue; 18) identify placental epigenetic mechanisms that affect fetal nutrition, growth and development; 19) determine how programming of glucose intolerance, obesity, and the epigenetic dysregulation of skeletal muscle-growth in mice is affected by maternal diet during development; 20) determine if epigenetic programming and reprogramming contribute to lineage-specific patterns of gene expression; 21) develop targested knock-in mouse model to determine if nutrients can modulate hypermethylation, epigenetic silencing and increase susceptibility to disease; 22) evaluate leukocyte patterns, gene expression profiles, and inflammatory mediators in adipose tissue under influence of diatary manipulation that leads to obesity.
The research will be accomplished using a variety of animal models and scientific tools to simulate the human newborn and/or child. Animal models will be used to understand the central and peripheral circadian clock mechanisms that influence eating behavior, metabolism, and energy balance. Newborm animal models will be used to examine the effect of chronic parenteral nutrition during the neonatal period on glucose tolerance, insulin sensitivity, and body composition during late infancy and adolescence. Researchers will investigate the effects of intermittent bolus feeding versus continuous feeding, delivered either enterally or parenterally, on protein synthesis in neonatal animal models. This will allow our team to determine the long-term impact of these feeding modalities on growth and body composition. Various models will be placed on obesigenic diets at 5-6 weeks of age and evaluated at 7 days, 5 weeks, and 6 months to define a blood leukocyte expression profile at these time points. Children's Nutrition Research Center scientists will also characterize the functions of intracellular systems in the liver and their influences on the onset of fatty liver disease and glucose homeostasis. Additional investigation will occur on the intracellular signaling pathways of GLP-2 and their metabolic effects on food intake, energy expenditure, and glucose homeostasis.
Various mouse models, and a human model of epigenetic dysregulation compromising placental development, will be used to test if maternal obesity and fetal nutrition during development affects the establishment of gene-specific DNA methylation patterns in the developing fetus, which would cause permanent changes in gene expression, metabolism, food intake regulation, and body weight. Additionally we will investigate the mechanisms regulating DNA methylation during development, and characterize their involvement in nutritional programming during critical ontogenic periods. We will characterize the role of ghrelin and its receptor in nutritional regulation of energy and glucose homeostasis.