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

Location: Children's Nutrition Research Center

2017 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. New generation lipid emulsions improve metabolic function in parenterally fed neonates. Many premature infants cannot tolerate normal oral feeding and instead require a life-saving therapy called parenteral nutrition (PN). In the U.S., the main lipid emulsion used in infant PN is based on soybean oil and babies that remain on this emulsion for a long period develop parenteral nutrition-associated liver disease (PNALD), which can be life-threatening. Researchers in Houston, Texas tested in premature, newborn animal models, two new lipid emulsions - pure-fish oil or a mixture that contained soybean oil, medium chain triglycerides and olive and fish oils. The results showed that the models on the two new emulsions improved the ability to use glucose by enhancing the body's response to insulin. These findings are important and show that these new lipid emulsions may improve the ability of premature infants to grow normally.

2. Cellular signaling pathway that mediates obesity. Brain mechanisms that link diet and obesity are not fully understood. Researchers in Houston, Texas recently identified a novel signaling pathway that actively responds to high-fat diet feeding and mediates leptin resistance, obesity and glucose imbalance. Consuming a high-fat diet results in changes in the brain that lead to a decreased sensitivity to leptin, the 'satiety hormone' that helps regulate body weight by inhibiting appetite. We examined the role of a signaling molecule called Rap1 in body weight control and glucose balance and found that mice lacking the Rap 1 gene did not gain body fat when fed a high-fat diet. This new mechanism involving Rap1 in the brain may represent a potential therapeutic target for treating human obesity in the future.

3. Supplementation with a leucine enhances muscle protein synthesis in neonates. Many infants born in the U.S. are low birth weight and most experience extrauterine growth restriction by hospital discharge. Current feeding strategies are often unable to provide adequate nutrition and thus the development of new strategies to optimize growth is needed. Researchers in Houston, Texas showed that supplementation with a leucine metabolite, beta-hydroxy-beta-methybutyrate, increased protein synthesis in muscle and stimulated the proliferation of muscle stem cells. These results suggest that this leucine metabolite merits consideration as a nutritional supplement to enhance protein synthesis and muscle growth in neonates.

4. Arginine synthesis is functional during the neonatal period. Arginine is an essential amino acid for preterm infants since their bodies are unable to synthesize it internally in sufficient amounts. Scientists previously thought that, because all the components necessary for arginine production are present in the neonatal gut, the small intestine produced arginine, but not citrulline during this age period. Researchers in Houston, Texas have shown that the collaboration between the intestine and kidney produce arginine in neonatal pigs, which is not different from adult animals. This demonstrates that the intestine is not critical for arginine synthesis from citrulline in the neonate and that during this period pigs can benefit from citrulline supplementation, even when intestinal metabolism is impaired. This work opens the possibility of supplementing citrulline to premature infants to support their arginine needs.

5. The role of circadian dysfunction in metabolic syndrome and cancer. Researchers are attempting to answer if chronic circadian disruption alone leads to obesity and cancer. Scientists in Houston, Texas conducted research that demonstrated that chronic circadian disruption alone is sufficient to induce metabolic syndrome, fatty liver disease, and cancer. Chronic circadian disruption is affecting the majority people in the U.S. now due to lifestyle changes. Our findings lead to a better understanding of how unhealthy lifestyle factors can increase the risk of obesity and cancer, and will lead to development of novel strategies for obesity and cancer prevention and treatment.

6. High fat diet induces changes in the cornea. It is known that diabetics have detrimental changes in the surface of the eye, however we aim to determine if changes in the cornea occur before a high fat diet begins to induce a prediabetic condition. Researchers in Houston, Texas conducted research that showed that within 10 days on a high fat diet, prior to any evidence of diabetic changes, mice exhibited detrimental changes in the cornea. These findings are significant and promote a heightened awareness of early and possibly reversible corneal changes in individuals prone to eating a high fat diet, allowing dietary intervention that promotes ocular health.

Review Publications
Kettner, N.M., Volcu, H., Finegold, M.J., Coarfa, C., Sreekumar, A., Putluri, N., Katchy, C.A., Lee, C., Moore, D.D., Fu, L. 2016. Circadian homeostatis of liver metabolism suppresses hepatocarcinogenesis. Cancer Cell International. 30:909-924.
Agarwal, U., Didelija, I.C., Yuan, Y., Wang, X., Marini, J.C. 2017. Supplemental citrulline is more efficient than arginine to increase systemic arginine availability in mice. Journal of Nutrition. 147(4):596-602.
Marini, J.C., Agarwal, U., Didelija, I.C., Azamian, M., Stoll, B., Nagamani, S.C. 2017. Plasma glutamine is a minor precursor for the synthesis of citrulline: A multispecies study. Journal of Nutrition. 147(4):549–555.
Hernandez-Garcia, A., Manjarin, R., Suryawan, A., Nguyen, H.V., Davis, T.A., Orellana, R.A. 2016. Amino acids, independent of insulin, attenuate skeletal muscle autophagy in neonatal pigs during endotoxemia. Pediatric Research. 80:448–451. doi:10.1038/pr.2016.83.
Manjarin, R., Suryawan, A., Koo, S.J., Wilson, F.A., Nguyen, H.V., Davis, T.A., Orellana, R.A. 2016. Insulin modulates energy and substrate sensing and protein catabolism induced by chronic peritonitis in skeletal muscle of neonatal pigs. Pediatric Research. 80(5):744-752.
Hernandez-Garcia, A.D., Columbus, D.A., Manjarin, R., Nguyen, H.V., Suryawan, A., Orellana, R.A., Davis, T.A. 2016. Leucine supplementation stimulates protein synthesis and reduces degradation signal activation in muscle of newborn pigs during acute endotoxemia. American Journal of Physiology - Endocrinology and Metabolism. 311(4):E791-E801.
Kaneko, K., Xu, P., Cordonier, E.L., Chen, S.S., Ng, A., Xu, Y., Morozov, A., Fukuda, M. 2016. Neuronal Rap1 regulates energy balance, glucose homeostasis, and leptin actions. Cell Reports. 16:3003-3015.
Zhang, W., Magadi, S., Li, Z., Smith, C., Burns, A.R. 2016. IL-20 promotes epithelial ealing of the injured mouse cornea. Experimental Eye Research. 154:22-29.
Wu, N., Kim, K., Zhou, Y., Lee, J., Kettner, N.M., Mamrosh, J.L., Choi, S., Fu, L., Moore, D.D. 2016. Small heterodimer partner (NROB2) coordinates nutrient signaling and the circadian clock in mice. Molecular Endocrinology. 30(9):988-995.
Aunsholt, L., Qvist, N., Sanglid, P.T., Vegge, A., Stoll, B., Burrin, D.G., Jeppesen, P.B., Ericksen, T., Husby, S., Thymann, T. 2017. Minimal enteral nutrition to improve adaptation after intestinal resection in piglets and infants. Journal of Parenteral and Enteral Nutrition. doi:10.1177/0148607117690527.
Yang, L., Achreja, A., Yeung, T., Mangala, L.S., Jiang, D., Han, C., Baddour, J., Marini, J.C. 2016. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metabolism. 24(5):685-700.
Fleet, T., Stashi, E., Zhu, B., Rajapakshe, K., Marcelo, K.L., Kettner, N.M., Gorman, B.K., Coarfa, C., Fu, L., O'Malley, B.W., York, B. 2016. Genetic and environmental models of circadian disruption link SRC-2 function to hepatic pathology. Journal of Biological Rhythms. 31(5):443-460.
Nichols, B.L., Avery, S.E., Quezada-Calvillo, R., Kilani, S.B., Lin, A.H., Burrin, D.G., Hodges, B.E., Chacko, S.K., Opekun, A.R., Hindawy, M.E., Hamaker, B.R., Oda, S.I. 2017. Improved starch digestion of sucrase deficient shrews treated with oral glucoamylase enzyme supplements. Journal of Pediatric Gastroenterology and Nutrition. doi:10.1097/MPG.0000000000001561.
Didelija, I.C., Mohammad, M.A., Marini, J.C. 2017. Ablation of arginase II spares arginine and abolishes the arginine requirement for growth in male mice. Journal of Nutrition. 147(8):1510-1516.
Martin, C.R., Stoll, B., Cluette-Brown, J., Akinkuotu, A.C., Olutoye, O.O., Gura, K., Singh, P., Zaman, M.M., Perillo, M.C., Puder, M., Freedman, S.D., Burrin, D.G. 2017. Use of a novel docosahexaenoic acid formulation vs control in a neonatal porcine model of short bowel syndrome leads to greater intestinal absorption and higher systemic levels of DHA. Nutrition Research. 39:51-60.
Marini, J.C., Agarwal, U., Robinson, J.L., Yuan, Y., Didelija, I.C., Stoll, B., Burrin, D.G. 2017. The intestinal-renal axis for arginine synthesis is present and functional in the neonatal pig. American Journal of Physiology - Endocrinology and Metabolism. doi:10.1152/ajpendo.00055.2017.
Jordan, K., Pontoppidan, P., Uhlving, H.H., Kielsen, K., Burrin, D.G., Weischendorff, S., Christensen, I.J., Jorgensen, M.H., Heilmann, C., Sengelov, H., Muller, K. 2017. Gastrointestinal toxicity, systemic inflammation, and liver biochemistry in allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation. 23(7):1170-1176.
Guthrie, G., Premkumar, M., Burrin, D.G. 2017. Emerging clinical benefits of new generation fat emulsions in preterm neonates. Nutrition in Clinical Practice. 32(3):326-336.
Raiten, D.J., Steiber, A.L., Carlson, S.E., Griffin, I., Anderson, D., Hay, Jr., W.W., Robins, S., Neu, J., Georgieff, M.K., Groh-Wargo, S., Fenton, T.R., Pre-B Consultative, W., Burrin, D.G. 2016. Working group reports: Evaluation of the evidence to support practice guidelines for nutritional care of preterm infants-the Pre-B Project. American Journal of Clinical Nutrition. 103(2):648S-78S. doi:10.3945/ajcn.115.117309.
Guthrie, G., Tackett, B., Stoll, B., Martin, C., Olutoye, O., Burrin, D.G. 2017. Phytosterols synergize with endotoxin to augment inflammation in Kupffer cells but alone have limited direct effect on hepatocytes. Journal of Parenteral and Enteral Nutrition. doi:10.1177/0148607117722752.