Location: Children's Nutrition Research Center
2019 Annual Report
Objectives
Our goal is to identify strategies to optimize the nutrition and health of infants and their development. We will: 1) determine the effect of enteral nutrition on the downstream signaling pathways and metabolism in various tissues; 2) determine if increased FGF19 availability controls the rate of growth, tissue protein synthesis and intestinal development; 3) determine if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4) identify by which amino acids, regulate protein synthesis, degradation, and accretion and how these responses change with age; 5) identify the mechanisms that limit citrulline production; determine the basis for the greater citrulline production observed in females and determine the utilization of citrulline for endogenous arginine synthesis at different stages; 6) study the molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts; 7) determine the impact of maternal dietary protein level during lactation; 8) determine if vitamin D receptors in the brain are critical for glucose regulation; 9) determine if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A or B reduces the rates of gluconeogenesis; 10) study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway; 11) alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and physical activity; isolate specific neuronal (and potentially non-neuronal) hypothalamic cell types to evaluate cell type-specific alterations in DNA methylation in established models of nutritional programming; 12) find the causes of interindividual epigenetic variation and consequences for human energy balance; identify human metastable epialleles that predict risk of obesity; assess how DNA methylation at obesity-associated metastable epialleles is affected by maternal periconceptional nutrition; 13) determine the functional impact of folic acid supplementation and in intestinal carcinogenesis; 14) study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone microarchitecture, bone biomarkers and endothelial function; 15) evaluate the effect of high dose vitamin D therapy on change in bone microarchitecture, restoration of bone biomarkers balance and endothelial function; and 16) determine anthropometry and body composition, total dietary energy intake, total energy expenditure, energy balance, biomarkers of cardiovascular health and early risk factors for Type 2 diabetes.
Approach
This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function.
Progress Report
To review the progress made during the year, please refer to the following
projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), and
3092-51000-065-03S (Project #3).
Accomplishments
