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United States Department of Agriculture

Agricultural Research Service

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Location: Houston, Texas

2012 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.

3. Progress Report:
In Obj. 1A, we have extended our work to examine the underlying mechanisms whereby chronic parenteral nutrition (PN) induces metabolic dysfunction. This dysfunction was marked by accumulation of fat in the liver and a condition of glucose intolerance known as insulin resistance. Insulin triggers cells to take up glucose from the blood and use it for energy, and insulin resistance leads to increased blood glucose similar to what happens in adolescents who have type 2 diabetes. In this most recent study, we used neonatal piglets (as a model for an infant) to further test how feeding patterns contribute to these metabolic dysfunctions. We compared piglets fed either intravenous or enteral nutrition, continuous or intermittent nutrition, or polymeric or elemental nutrition. The latter comparison tested normal cow's milk formula with a mixture of purified nutrients that were both matched to the same nutritional content. Our results showed that the intermittent feeding pattern produced the optimum metabolic function and was more important than if feeding occurred by the enteral vs. PN route. Additionally, the optimal metabolic function was associated with increased secretion of key gut hormones that improved insulin sensitivity. This work was recently published in the Journal of Parenteral and Enteral Nutrition. These findings are especially important because they complement and confirm our research results, which suggest that the pattern of nutrition is an important determinant of the metabolic response to insulin. Collectively, these studies suggest that intermittent or bolus feeding is a more optimal feeding approach than continuous feeding. Also related to Obj. 1A, we have continued progress on the study designed to examine the long-term effects of enteral and parenteral nutrition in neonatal, term piglets. We reported preliminary results last year that neonatal PN, increased body fat content after the first two postnatal weeks of PN and this persisted up to 8 weeks even after the pigs in the PN and enteral fed groups were fed the same diet. Further analysis shows that there were no differences in glucose tolerance based on an intravenous glucose tolerance test, nor were there any differences in serum metabolite analysis that would suggest liver disease or dyslipidemia. We disseminated these findings in two oral presentations and published two abstracts at national meetings this year. We have also continued work on a study designed to examine the impact of new generation parenteral lipid emulsions on metabolic function and prevention of liver disease in preterm PN-fed piglets. This project has generated highly clinically relevant results showing that fish-oil containing lipid emulsions prevent liver disease. We are finalizing this project and plan to submit a manuscript in the next month. This project also forms the basis for a NIH grant application that was submitted this in July. Recent findings from this project were disseminated in an oral presentation and published abstract at a national meeting this year. In Obj. 1B, we have completed the study designed to test the effect of the trophic gut hormone, glucagon-like peptide 2 (GLP-2) pretreatment on the incidence of necrotizing enterocolitis (NEC), commonly seen in premature infants where intestinal tissue dies. Our results showed that GLP-2 pretreatment delays the onset, but does not prevent the incidence of NEC in our preterm piglet model. This finding is disappointing and may be related to the short duration of GLP-2 treatment prior to enteral formula feeding. Given these results, we have elected not to continue on Obj.1B with studies designed to test whether GLP-2 pretreatment improves digestive function in preterm total parenteral nutrition (TPN)-fed piglets. In collaborative studies related to GLP-2 function, we recently completed a study that demonstrated a novel action of enteral bile acid treatment in prevention of PN-related mucosal atrophy and liver disease. This work was accomplished in collaboration with other BCM researchers, and showed that treatment of PN-fed piglets with enteral bile acid prevents the development of hepatic cholestasis and steatosis and reversed the mucosal atrophy. This work was published in the American Journal of Physiology. This project forms the basis for an NIH grant application that was submitted in July. In Obj. 2A, the mechanisms by which amino acids regulate protein synthesis in neonates was examined. In studies that our laboratory recently published in Pediatric Research we showed that supplementation of a milk formula with the branched-chain amino acid leucine enhances protein synthesis in skeletal muscles of different fiber types as well as in visceral tissues of neonatal pigs. This increase in protein synthesis is due to up-regulation of the intracellular signaling pathway that regulates translation initiation. The results suggest that leucine supplementation of a milk formula may have beneficial effects on the growth of low-birth-weight infants. In studies to address Obj. 2B (published in the Journal of Nutrition), we showed that intermittent bolus feeding has a greater stimulatory effect on protein synthesis in skeletal muscle as compared to continuous feeding in neonates. This greater increase in protein synthesis is due to the more rapid and profound increases in circulating amino acids and insulin that activate the intracellular signaling proteins that regulate translation initiation. Furthermore, we showed in studies published in the American Journal of Physiology – Endocrinology and Metabolism that the enhanced rate of muscle protein synthesis results in an increase in protein deposition in skeletal muscle but protein degradation is insensitive to feeding frequency. Studies to address Obj. 2C are being conducted to examine the long-term effects of intermittent bolus feeding vs. continuous feeding on growth. These results show that intermittent feeding enhances lean tissue accretion as compared to continuous feeding by increasing the efficiency with which the formula is used for lean growth. Studies are being completed to identify the intracellular mechanisms that mediate the response to these modes of nutritional support.

4. Accomplishments

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