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

Location: Children's Nutrition Research Center

2018 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. Lactose is the optimal dietary carbohydrate to prevent preterm infant disease. Necrotizing enterocolitis (NEC) is a very devastating, serious disease found in newborns that causes an inflammatory process that leads to intestinal damage and sometimes death. Researchers in Houston, Texas, using preterm animal models, previously showed that feeding formula containing the sugar lactose protected them from NEC. In comparison, those fed formula containing corn syrup solids had a higher risk of developing the condition. In this study, we found that the communities of bacteria were not dramatically different between the lactose and the corn syrup solids group, but the metabolite profiles were very different. These findings suggest that lactose is the optimal sugar to include in preterm infant formula and that inclusion of corn syrup solids should be reconsidered.

2. MMP12 enzyme participates in high fat diet induced inflammation. A high fat diet causes an abnormal increase in fat tissues of white blood cells that are normally involved in fighting infection. The mechanisms involved in this response are poorly understood. Researchers in Houston, Texas demonstrated that when mice are deficient in Matrix Metalloproteinase 12, a tissue remodeling enzyme, this high fat diet induced adipose inflammation is reduced. This result increases our understanding of another mechanism contributing to the diet induced inflammatory process.

Review Publications
Sun, J., Li, Y., Nguyen, D., Mortensen, M.S., Van Den Akker, C., Skeath, T., Pors, S.E., Pankratova, S., Rudloff, S., Sorensen, S.J., Burrin, D.G., Thymann, T., Sangild, P.T. 2018. Nutrient fortification of human donor milk affects intestinal function and protein metabolism in preterm pigs. Journal of Nutrition. 148(3):336-347.
Wagner, M., Choi, S., Panzitt, K., Mamrosh, J.L., Lee, J.M., Zaufel, A., Xiao, R., Wooton-Kee, R., Stahlman, M., Newgard, C.B., Boren, J., Moore, D.D. 2016. Liver receptor homolog-1 is a critical determinant of methyl-pool metabolism. Hepatology. 63(1):95-106.
Call, L., Stoll, B., Oosterloo, B., Ajami, N., Sheikh, F., Wittke, A., Waworuntu, R., Berg, B., Petrosino, J., Olutoye, O., Burrin, D.G. 2018. Metabolic signatures distinguish the impact of formula carbohydrates on disease outcome in a pretern piglet model of NEC. BMC Microbiome. 6:111.
Shi, X., Chacko, S., Li, F., Li, D., Burrin, D., Chan, L., Guan, X. 2017. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity. Molecular Metabolism. 6(11):1350-1359.
Fiorotto, M.L., Davis, T.A. 2018. Critical windows for the programming effects of early-life nutrition on skeletal muscle mass. In: Colombo., Koletzko, B., Lampl, M., editors. Resent Research in Nutrition. 89th volume. Basil, Switzerland: Karger. p. 25-35.
Manjarin, R., Columbus, D.A., Solis1, J., Hernandez-Garcia, A.D., Suryawan, A., Nguyen, H.V., McGuckin, M.M., Jimenez, R.T., Fiorotto, M.L., Davis, T.A. 2018. Short- and long-term effects of leucine and branched-chain amino acid supplementation of a protein- and energy-reduced diet on muscle protein metabolism in neonatal pigs. Amino Acids. 50(7):943-959.
Nagamani, S.C., Agarwal, U., Tam, A., Azamian, M., McMeans, A., Didelija, I.C., Mohammad, M.A., Marini, J.C. 2017. A randomized trial to study the comparative efficacy of phenylbutyrate and benzoate on nitrogen excretion and ureagenesis in healthy volunteers. Genetics in Medicine.
Yuan, Y., Mohammad, M., Betancourt, A., Didelija, I.C., Yallampalli, C., Marini, J.C. 2018. The citrulline recycling pathway sustains cardiovascular function in arginine-depleted healthy mice, but cannot sustain nitric oxide production during endotoxin challenge. Journal of Nutrition. 148(6):844–850.
Lykke, M., Sangild, P.T., Van Goudoever, J.B., Van Harskamp, D., Schierbeek, H., Koletzko, B., Van Der Beek, E.M., Abrahamse-Berkeveld, M., Van De Heijning, B., Stoll, B., Burrin, D.G., Thymann, T. 2018. Growth and clinical variables in nitrogen-restricted piglets fed an adjusted essential amino acid mix: Effects using free amino acid-based diets. Journal of Nutrition. 148(7):1109-1117.
Worsoe, P.S., Sangild, P.T., Van Goudoever, J.B., Koletzko, B., Van Der Beek, E.M., Abrahamse-Berkeveld, M., Burrin, D.G., Van De Heijning, B., Thymann, T. 2018. Growth and clinical variables in nitrogen-restricted piglets fed an adjusted essential amino acid mix: Effects using partially intact protein-based diets. Journal of Nutrition. 148(7):1118-1125.
Duerrschmid, C., He, Y., Wang, C., Li, C., Bournat, J., Romere, C., Saha, P., Lee, M., Phillips, K., Jia, P., Zhao, Z., Farias, M., Wu, Q., Milewicz, D., Sutton, R., Moore, D., Butte, N., Krashes, M., Xu, Y., Chopra, A. 2017. Asprosin is a centrally acting orexigenic hormone. Nature Medicine.
Suryawan, A., Davis, T.A. 2018. Amino acid- and insulin-induced activation of mTORC1 in neonatal piglet skeletal muscle involves sestin2-GATOR2, Rag A/C-mTOR, and RHEB-mTOR complex formation. Journal of Nutrition. 148:825-833.
Sun, J., Li, Y., Pan, X., Nguyen, D., Brunse, A., Bojesen, A., Rudloff, S., Mortensen, M., Burrin, D., Sangild, P. 2018. Human milk fortification with bovine colostrum is superior to formula-based fortifier to prevent gut dysfunction, necrotizing enterocolitis, and systemic infection in preterm pigs. Journal of Parenteral and Enteral Nutrition.