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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Research Project #426348

Research Project: Molecular, Cellular, and Regulatory Aspects of Nutrition During Development

Location: Children's Nutrition Research Center

2015 Annual Report

The goal of this research is to identify strategies to optimize the nutrition and health of infants and their development. CNRC researchers will: 1) investigate the impact of perinatal nutrition in the model system of premature piglets on the prevention of parenteral nutrition-associated liver disease (PNALD) and necrotizing enterocolitis (NEC); 2) define the role of liver receptor homolog-1 (LRH-1) as a factor in hepatic lipotropic responses, including the influence of methionine/choline deficient diets (MCD); 3) characterize the effect of the loss of hepatic LRH-1 in the lipotropic response to methyl pool supplementation in the standard mouse model of diet induced obesity; 4) determine the influence of leucine supplementation in stimulating protein synthesis, enhancing lean growth, and reducing protein degradation in healthy neonatal piglets and during catabolic conditions such as sepsis; 5) determine whether the deficit in lean deposition incurred with continuous as compared to intermittent bolus feeding during the neonatal period can be prevented by leucine supplementation or recuperated by initiation of intermittent bolus feeding; 6) determine whether citrulline plasma concentration is an early indicator for gut immaturity and gut dysfunction in a piglet model of prematurity; 7) determine if arginine and citrulline supplementation are able to reduce the incidence of necrotizing enterocolitis; 8) identify the cellular signaling networks that modify leptin-signal transducer and activator of transcription 3 (STAT3) signaling and potentially contribute to leptin resistance; 9) determine, using genetically engineered mouse models, the role of a cellular leptin signaling modifier in high fat diet-induced leptin resistance and subsequent alterations in energy and glucose homeostasis, and adiposity; 10) study the mechanism of circadian dysfunction-induced leptin resistance and the role of leptin resistance in obesity development; 11) determine the contributions of alpha Beta and yoT cells to inflammation in skeletal muscle; 12) determine the mechanisms leading to early anti-inflammatory macrophage polarization in mesenteric adipose tissue and the peritoneal cavity of C57BL/6J mice; 13) define how tissue healing is dysregulated in Western-style diet-induced obesity; 14) determine if Matrix Metalloproteinase 12 influences the development of insulin resistance and tissue inflammation in the context of high fat, Western-type diet-induced obesity; 15) determine if Matrix Metalloproteinase 12 influences white adipose tissue extracellular matrix remodeling under conditions of Western-type diet feeding.

The research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will perform tissue transcriptomic profiling to identify novel genes, gene networks and metabolic pathways that are differentially affected by two lipid emulsions. We will also quantify expression of targeted genes involved in hepatic bile acid metabolism. In mouse models, physiologic studies will be performed that will include analysis of serum and hepatic levels of trigylcerides, free fatty acids, total cholesterol and total phosphatidylcholine. Using porcine models, we will perform protein synthesis experiments in leucine-infused endotoxemic pigs. Additionally we will use porcine models to determine if arginine and citrulline supplementation reduces the incidence of necrotizing enterocolitis. CNRC researchers will also employ an ex vivo model to determine if STAT3 signaling acts as a signaling hub for distinct signaling pathways mediating cellular leptin resistance. Complicated studies will be performed to study the mechanism of reciprocal interactions between the central circadian clock and hypothalamic arcuate nucleus in maintaining homeostasis of leptin signaling. Researchers will also study the role of circadian dysfunction of sympathetic nervous system (SNS) signaling in the development of leptin resistance and diet-induced obesity. And finally scientists will use a murine model (that develops chronic inflammation similar to that observed in obese humans) of diet-induced obesity and will use short- and long-term feeding techniques for the localization and phenotypic characterization of lymphocytes in skeletal muscle, and techniques for depletion of lymphocyte subsets.

Progress Report
Significant research progress was accomplished during the year. To review the progress, please refer to project 3092-51000-060-01S (Project #1), 3092-51000-060-02S (Project #2), and 3092-51000-060-03S (Project #3).

1. Vitamin E protects against liver damage. Many premature infants are fed by intravenous nutrition support (TPN) in order to survive and grow but the lipid component of TPN has been linked to pediatric liver disease. Children's Nutrition Research Center researchers in Houston, TX had previously showed that newer lipid emulsions prevent liver disease because of differences in the vitamin E or phytosterol content. Using premature, TPN-fed piglets as a model for human infants, we found that adding the vitamin E to the currently approved lipid solution prevented liver disease, but adding phytosterols to new lipid emulsions did not result in liver damage. These results challenge the idea that phytosterols cause liver disease and show that vitamin E is protective and may explain the benefit of new lipid emulsions.

2. Circadian disruption increases the risk of obesity. Obesity continues to be a significant concern and is more prevalent in individuals that perform shift-work due a disruption in their circadian clock. Children's Nutrition Research Center scientists in Houston, TX reported that frequent disruption of the circadian homeostasis, which has reached epidemic levels in the U.S., can directly increase fat gain independent of all previously identified obesity risk factors, such as gene mutation, diet components and the amount of physical exercise. This discovery, will have a significant impact on obesity research and will support the development of more efficient weight watching programs for obesity prevention.

3. Specific white blood cells cause tissue injury when a high fat diet is consumed. Scientists sought to know if a certain type of white blood cells (gamma/delta T cells) are involved in tissue injury induced by a high fat diet? Children's Nutrition Research Center scientists in Houston, TX conducted research that showed that mice fed a diet rich in milk fat developed tissue injury and increased insulin resistance. Both developments are indicators of a pre-diabetic condition and that gamma/delta T cells are necessary for this effect of the diet. This finding is important as it provides an increased understanding of factors that lead to type II diabetes in a high percentage of obese individuals.

Review Publications
Huang, L., Belousova, T., Szu-Chin Pan, J., Du, J., Ju, H., Lu, L., Zhang, P., Truong, L.D., Nuotio-Antar, A., Sheikh-Hamad, D. 2014. AKI after conditional and kidney-specific knockdown of Stanniocalcin-1. Journal of the American Society of Nephrology. 2(10):2303-2315.
Mehta, P., Nuotio-Antar, A.M., Smith, C. 2015. Gamma delta T cells promote inflammation and insulin resistance during high fat diet-induced obesity in mice. Journal of Leukocyte Biology. 97:121-134.
Suryawan, A., Davis, T.A. 2015. Enteral leucine and protein synthesis in skeletal and cardiac muscle. In: Rajendram, R., Preedy, V.R, Patel, V.B., editors. Branched Chain Amino Acids in Clinical Nutrition. 1st edition. New York, NY: Springer. p. 197-210.
Sanglid, P., Ney, D.M., Sigalet, D.L., Vegge, A., Burrin, D.G. 2014. Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: Translational relevance and challenges. American Journal of Physiology - Gastrointestinal and Liver Physiology. 307(12):G1147-G1168.
Kettner, N.M., Mayo, S.A., Hua, J., Choogon, L., Moore, D.L., Fu, L. 2015. Circadian dysfunction induces leptin resistance in mice. Cell Metabolism. 22:1-12.
Witte, N., Muenzner, M., Rietscher, J., Knauer, M., Heidenreich, S., Nuotio-Antar, A.M., Graef, F.A., Fedders, R., Tokachov, A., Goehring, I., Schupp, M. 2015. The glucose sensor ChREBP links de-novo lipogenesis to PPARgamma activity and adipocyte differentiation. Endocrinology.
Wheatley, S.M., El-Kadi, S.W., Suryawan, A., Boutry, C., Orellana, R.A., Nguyen, H.V., Davis, S.R., Davis, T.A. 2014. Protein synthesis in skeletal muscle of neonatal pigs is enhanced by administration of Beta-hydroxy-Beta-methylbutyrate. American Journal of Physiology - Endocrinology and Metabolism. 306(1):E91-99.
Layman, D.K., Anthony, T.G., Rasmussen, B.B., Adams, S.H., Lynch, C.J., Brinkworth, G.D., Davis, T.A. 2015. Defining meal requirements for protein to optimize metabolic roles of amino acids. American Journal of Clinical Nutrition. 101(Suppl):1330S-1338S.
Davis, T.A., Fiorotto, M.L., Suryawan, A. 2015. Bolus vs. continuous feeding to optimize anabolism in neonates. Current Opinion in Clinical Nutrition and Metabolic Care. 18(1):102-108.
Zamora, I.J., Stoll, B., Ethun, C.G., Sheikh, F., Yu, L., Burrin, D.G., Brandt, M.L., Olutoye, O.O. 2015. Low abdominal NIRS values and elevated plasma intestinal fatty acid-binding protein in a premature piglet model of necrotizing enterocolitis. PLoS One. 10(6):e0125437. doi:10.1371/journal.pone.0125437.
Ghoneim, N., Bauchart-Thevret, C., Oosterloo, B., Stoll, B., Kulkarni, M., Saenz De Pipaon, M., Zamora, I.J., Olutoye, O.O., Berg, B., Wittke, A., Burrin, D.G. 2014. Delayed initiation but not gradual advancement of enteral formula feeding reduces the incidence of necrotizing enterocolitis (NEC) in preterm pigs. PLoS One. 9(9):e106888. doi: 10.1371/journal.pone.0106888.
Jain, A.K., Wen, J.X., Arora, S., Blomenkamp, K.S., Rodrigues, J., Blaufuss, T.A., Liou, V., Burrin, D.G., Long, J.P., Teckman, J.H. 2014. Validating hyperbilirubinemia and gut mucosal atrophy with a novel ultramobile ambulatory total parenteral nutrition piglet model. Nutrition Research. 35(2):169-174.
Patel, A.K., Lazar, D.A., Burrin, D.G., Smith, E., Magliaro, T.J., Stark, A.R., Brandt, M.L., Zamora, I.J., Sheikh, F., Akinkuotu, A.C., Olutoye, O.O. 2014. Abdominal near-infrared spectroscopy measurements are lower in preterm infants at risk for necrotizing enterocolitis. Pediatric Critical Care Medicine. 15(8):735-741.
Marini, J.C., Agarwal, U., Didelija, I. 2015. Dietary arginine requirements for growth are dependent on the rate of citrulline production in mice. Journal of Nutrition. 145(6):1227-1231.
Marini, J.C., Didelija, I. 2015. Arginine depletion by arginine deiminase does not affect whole protein metabolism or muscle fractional protein synthesis rate in mice. PLoS One. 10(3):e0119801. doi:10.1371/journal.pone.0119801.
Jia, L., Vianna, C.R., Fukuda, M., Berglund, E.D., Liu, C., Tao, C., Sun, K., Liu, T., Harper, M.J., Lee, C.E., Lee, S., Scherer, P.E., Elmquist, J.K. 2014. Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nature Communications. 5:3878.
Marini, J.C., Didelija, I.C., Fiorotto, M.L. 2014. Extrarenal citrulline disposal in mice with impaired renal function. American Journal of Physiology - Renal Physiology. 307(6):F660-F665.
Williams, K.W., Liu, T., Kong, X., Fukuda, M., Deng, Y., Berglund, E.D., Deng, Z., Gao, Y., Liu, T., Sohn, J., Jia, L., Fujikawa, T., Kohno, D., Scott, M.M., Lee, S., Lee, C.E., Sun, K., Chang, Y., Scherer, P.E., Elmquist, J.K. 2014. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metabolism. 20(3):471-482.
Wheatley, S.M., El-Kadi, S.W., Suryawan, A., Boutry, C., Orellana, R.A., Nguyen, H.V., Davis, S.R., Davis, T.A. 2014. Protein synthesis in skeletal muscle of neonates is enhanced by administration of beta-hydroxy-beta-methylbutyrate. American Journal of Physiology - Endocrinology and Metabolism. 306:E91-E99.
Fiorotto, M.L., Davis, T.A., Sosa, H.A., Villegas-Montoya, C., Estrada, I., Fleischmann, R. 2014. Ribosome abundance regulates the recovery of skeletal muscle protein mass upon recuperation from postnatal undernutrition in mice. Journal of Physiology. 592(Pt23):5269-5286.
Columbus, D.A., Fiorotto, M.L., Davis, T.A. 2014. Leucine is a major regulator of muscle protein synthesis in neonates. Amino Acids. 47(2):259-270.
Yan, C., Yang, Y., Saito, K., Xu, P., Wang, C., Hinton, A.O., Yan, X., Wu, Q., Tong, Q., Elmquist, J.K., Fukuda, M., Xu, Y. 2015. Meta-Chlorophenylpiperazine enhances leptin sensitivity in diet-induced obese mice. British Journal of Pharmacology. 172(14):3510-3521.
Zhu, L., Zou, F., Yang, Y., Xu, P., Saito, K., Hinton, A.O., Yan, X., Ding, H., Wu, Q., Fukuda, M., Sun, Z., Tong, Q., Xu, Y. 2015. Estrogens prevent metabolic dysfunctions induced by circadian disruptions in female mice. Endocrinology. 156(6):2114-2123.
Lin, L., Nuotio-Antar, A.M., Ma, X., Liu, F., Fiorotto, M.L., Sun, Y. 2014. Ghrelin receptor regulates appetite and satiety during aging in mice by regulating meal frequency and portion size but not total food intake. Journal of Nutrition. 144:1349-1355.
Burrin, D.G., Davis, T.A. 2014. Mechanisms of nutrient sensing. In: Ross, A.C., Caballero, B., Cousins, R.J., Tucker, K.L., Ziegler T.R., editors. Modern Nutrition in Health and Disease. 11th edition. Baltimore, MD: Lippincott Williams & Wilkens. p. 626-632.
Shen, R.L., Thymann, T., Ostergaard, M.V., Stoy, A.C., Krych, L., Nielsen, D.S., Lauridsen, C., Hartmann, B., Holst, J.J., Burrin, D.G., Sanglid, P.T. 2015. Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs. American Journal of Physiology - Gastrointestinal and Liver Physiology. 309(5):G310-G323.
Ng, K., Stoll, B., Chacko, S., Saenz De Pipaon, M., Lauridsen, C., Gray, M., Squires, E., Marini, J.C., Zamora, I.J., Olutoye, O.O., Burrin, D.G. 2015. Vitamin E in new-generation lipid emulsions protects against parenteral nutrition-associated liver disease in parenteral nutrition-fed preterm pigs. Journal of Parenteral and Enteral Nutrition. DOI: 10.1177/0148607114567900.
Wheatley, S.M., El-Kadi, S.W., Suryawan, A., Boutry, C., Orellana, R.A., Nguyen, H.V., Davis, S.R., Davis, T.A. 2013. Protein synthesis in skeletal muscle of neonatal pigs is enhanced by administration of beta-hydroxy-beta-methylbutyrate. Acarology International Congress Proceedings. 306(1):E91-E99.