2011 Annual Report
1a.Objectives (from AD-416)
Objective 1: Establish a model using caesarean-delivered animal model to investigate the impact of prematurity on the gastrointestinal and metabolic response to perinatal nutrition.
Subobjective 1A: Quantify the effect of chronic parenteral nutrition in the first 2 weeks after birth on the short-term (3 months) and long-term (12 months) development of body composition and glucose homeostasis in models delivered preterm and at term.
Subobjective 1B: Quantify whether manipulation of dietary macronutrients and supplementation with bioactive food ingredients fed to premature animal models prevents the onset of mucosal inflammation and gastrointestinal disease, specifically necrotizing enterocolitis.
Objective 2: Compare the impact of continuous versus intermittent bolus delivery of nutrients provided enterally or parenterally on protein synthesis and accretion in neonatal animal models and identify the intracellular signaling mechanism involved.
Subobjective 2A: Compare the short-term effects of enteral or parenteral amino acids provided in a continuous vs. intermittent bolus delivery pattern.
Subobjective 2B: Compare the short-term effects of an enteral or parenteral complete diet provided in a continuous vs. intermittent bolus delivery pattern.
Subobjective 2C: Compare the long-term effects of an enteral or parenteral complete diet provided in a continuous vs. intermittent bolus delivery pattern.
1b.Approach (from AD-416)
The goal of our research is to determine how key nutrients, bioactive ingredients, and the pattern of nutrient delivery affects nutrient metabolism, body composition and incidence of disease in early postnatal life. Children's Nutrition Research Center researchers will use multiple experimental approaches involving innovative neonatal animal models to specifically examine the effects of prematurity, parenteral nutrition, and intermittent bolus feeding versus continuous feeding on glucose and protein metabolism. Main endpoints of metabolism will include measurements of glucose tolerance and insulin sensitivity using hyperinsulinemic, euglycemic clamps. The metabolic fate of amino acids and glucose will be measured using oxidation and incorporation of stable isotopic tracers into end-products such as CO2 and protein. Our research team will also examine whether specific carbohydrates and treatment with the bioactive gut peptide, glucagon-like peptide-2, can prevent the onset of necrotizing enterocolitis using a novel premature animal model. We will quantify endpoints of gastrointestinal function, such as blood flow and nutrient absorption, as well as disease based on measures of proinflammatory cytokine expression and gut microbiota communities. This research will provide novel information that will be directly useful to optimize the nutritional management of low birth weight infants and reduce the risk of early postnatal diseases.
In Obj. 1A we aim to establish a model using caesarean-delivered animal models to study the impact of prematurity on the gut and metabolic response to perinatal nutrition. We completed and reported a study in term, neonatal animal models showing that parenteral vs. enteral nutrition results in poor metabolic condition marked by increased body fat, glucose intolerance, and inflammatory stress; published in the Journal of Nutrition. We initiated studies in premature animal models and established the capacity to deliver premature piglets via c-section, provide parenteral and enteral nutritional support for these animal models for 2 weeks. We are completing studies outlined in Obj. 1A to test if chronic parenteral nutrition in the first 2 weeks after birth affects the long-term development of body composition and glucose homeostasis in piglets delivered at term. Many premature infants are nourished by parenteral nutrition for weeks after birth. We designed the study to test if neonatal animal models given parenteral nutriton vs. enteral feeding for 2 weeks after birth have an increased risk for obesity and diabetes during adolescence. Due to logistical issues and funding, we used only term neonatal piglets and limited the study to 5-month duration. Preliminary results show that parenteral nutrition increased body fat content after 2 weeks of treatment, and this persisted for up to 8 weeks of age, even after the animal models were fed a common diet to the control enteral group. Previous studies demonstrated that muscle protein synthesis in neonates is profoundly sensitive to the availability of dietary amino acids. Studies in Obj. 2A examined the mechanisms by which amino acids regulate protein synthesis in neonates (published in Journal of Applied Physiology), and identified intracellular signaling proteins that mediate the stimulation of protein synthesis after a meal and differentiated those that are independently regulated by amino acids and insulin. Our studies showed that the ability of leucine to stimulate protein synthesis is specific for leucine and its immediate metabolite. We reported that continuous parenteral infusion of leucine stimulates protein synthesis by activating intracellular signaling proteins that regulate muscle and visceral protein synthesis. However, for prolonged stimulation, other amino acids also must be provided. Our studies showed that supplementation of formula with leucine increases protein synthesis. Our obj. 2B studies are currently being completed. We reported that intermittent bolus feeding stimulates protein synthesis by activating the signaling proteins that regulate protein synthesis, but the time course varies among tissues. Our results suggest that intermittent bolus feeding promotes greater muscle protein synthesis than continuous feeding by inducing a pulsatile pattern of amino acid- and insulin-induced translation initiation. Obj. 2C studies are being conducted to examine the long-term effects on muscle growth.
The ADODR monitors project activities by visits, review of purchases of equipment, review of ARS-funded foreign travel, and review of ARS funds provided through the SCA.
Feeding premature infants intravenously affects the infants' health and ability to regulate blood sugar levels. More than half a million infants are born prematurely in the United States every year, and for very-low-birth-weight infants that are unable to handle normal feeding by mouth, intravenous feeding, also known as total parenteral nutrition (TPN), becomes vital for life. However, no study with human infants has yet delineated a possible role of TPN in insulin resistance. Scientists at the Children's Nutrition Research Center in Houston, TX, conducted studies that revealed piglets given continuous TPN for their first two weeks of life were less able to control their blood glucose levels (by 40% less) than their orally fed counterparts, who were fed individual meals of milk-based formula four times a day. These findings are important for the pediatric community as it documents poor blood glucose control in newborns fed intravenously and suggests possible lifetime consequences.