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

Location: Children's Nutrition Research Center

2016 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. Pulsatile delivery of a leucine supplement enhances lean growth in neonates. Almost 8% of infants born in the U.S. are born of a low birth weight and optimizing their nutritional management is crucial for their immediate and long-term health and well-being. Low-birth-weight infants frequently are fed formula or human milk by gastric tube on either a continuous or intermittent bolus schedule. Researchers at the Children's Nutrition Research Center in Houston, Texas previously showed that intermittent bolus feeding enhances protein synthesis in skeletal muscle and promotes better lean growth than continuous feeding; however, due to feeding intolerance, some low-birth-weight infants must be fed continuously and, thus, alternative nutritional strategies are needed to improve their lean growth. We found that when neonatal piglets are continuously fed an optimal diet, further supplementation with pulses of the amino acid, leucine, enhances lean growth by stimulating muscle protein synthesis. These results suggest that leucine supplementation may be a useful nutritional therapy to enhance the efficiency with which nutrients are metabolized to improve lean growth.

2. The role of circadian control of leptin expression and signaling. Research studies focusing on the pathophysiological mechanism of body weight control is difficult and new efficient tools and techniques are in need to be developed or obtained. Researchers at the Children's Nutrition Research Center in Houston, Texas have developed new mouse models for studying the interaction between the brain and the fat tissues which are essential for maintaining the homeostasis of body weight control. Our team also developed a new technique that can be used to monitor the dynamic interaction of the central circadian clock with the hypothalamus energy homeostasis center. These tools will aid our understanding of the physiological role of circadian expression and signaling of leptin and these new tools and approaches will be invaluable to our understanding the pathophysiological mechanisms of circadian dynamics in disease prevention and treatment.

3. High fat diet has adverse effects on corneal health. Obese individuals have an increased risk of diminished visual acuity. Researchers at the Children's Nutrition Research Center in Houston, Texas conducted experiments designed to determine if the surface of the eye (cornea) is influenced adversely in animals fed a high fat diet. We found that a high fat diet resulted in: the normal daily cycle of white blood cells migrating through the tissue of the cornea failed to occur, nerves within the cornea became reduced in number and sensitivity to touch, and healing of surface wounds of the cornea, including the nerves within the cornea, was abnormal. These findings are important in researchers' efforts to understand why obesity is associated with increased abnormalities in vision and ocular health.

Review Publications
Nuotio-Antar, A.M., Poungvarin, N., Li, M., Schupp, M., Mohammad, M., Gerard, S., Zou, F., Chan, L. 2015. FABP4-Cre mediated expression of constitutively active ChREBP protects against obesity. Endocrinology. 11:4020-4032.
Buras, E., Yang, L., Saha, P., Kim, J., Mehta, P., Yang, Y., Hilsenbeck, S., Kojima, H., Chen, W., Smith, C.W., Chan, L. 2015. Proinsulin-producing, hyperglycemia-induced adipose tissue macrophages underlie insulin resistance in high fat-fed diabetic mice. Federation of American Societies for Experimental Biology Conference. 29:3537-3548.
Lam, F.W., Phillips, J., Landry, P., Magadi, S., Smith, C., Rumbaut, R.E., Burns, A.R. 2015. Platelet recruitment promotes keratocyte repopulation following corneal epithelial abrasion in the mouse. PLoS One. 29:3151-3159.
Nagy-Szakal, D., Mir, S., Harris, R., Dowd, S., Yamada, T., Lacorazza, H., Tatevian, N., Smith, C., De Zoeten, E., Klein, J., Kellermayer, R. 2015. Loss of n-6 fatty acid induced pediatric obesity protects against acute murine colitis. Journal of Federation of American Societies for Experimental Biology. 29:3151-3159.
Khan, I.M., Perrard, X., Perrard, J.L., Mansoori, A., Smith, C.W., Wu, H., Ballantyne, C.M. 2014. Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency. Atherosclerosis. 233(2):419-428.
Zhu, L., Xu, P., Cao, X., Yang, Y., Hinton, A., Xia, Y., Saito, K., Yan, X., Zou, F., Ding, H., Wang, C., Yan, C., Pradip, S., Khan, S.A., Zhao, J., Fukuda, M., Tong, Q., Clegg, D.J., Chan, L., Xu, Y. 2015. The ERa-PI3K cascade in proopiomelanocortin progenitor neurons regulates feeding and glucose balance in female mice. Endocrinology. 156(12):4474-4491.
Saito, K., He, Y., Yang, Y., Zhu, L., Wang, C., Xu, P., Hinton, A.O., Yan, X., Zhao, J., Fukuda, M., Tong, Q., Clegg, D.J., Xu, Y. 2016. PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. Scientific Reports. 6:23459.
Columbus, D.A., Steinhoff-Wagner, J., Suryawan, A., Nguyen, H.V., Hernandez-Garcia, A., Fiorotto, M.L., Davis, T.A. 2015. Impact of prolonged leucine supplementation on protein synthesis and lean growth in neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 309(6):601-610.
Boutry, C., El-Kadi, S.W., Suryawan, A., Steinhoff-Wagner, J., Stoll, B., Orellana, R.A., Nguyen, H.V., Kimball, S.R., Fiorotto, M.L., Davis, T.A. 2016. Pulsatile delivery of a leucine supplement during long-term continuous enteral feeding enhances lean growth in term neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 310(8):699-713.
Kao, M., Columbus, D.A., Suryawan, A., Steinhoff-Wagner, J., Hernandez-Garcia, A.D., Nguyen, H.V., Fiorotto, M., Davis, T. 2016. Enteral B-hydroxy-B-methylbutyrate supplementation increases protein synthesis in skeletal muscle of neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 310(11):1072-1084.
Yang, C., Yang, X., Lackeyram, D., Rideout, T.C., Wang, Z., Stoll, B., Yin, Y., Burrin, D.G., Fan, M.Z. 2016. Expression of apical Na(+)-L-glutamine co-transport activity, B(0)-system neutral amino acid co-transporter (B(0)AT1) and angiotensin-converting enzyme 2 along the jejunal crypt-villus axis in young pigs fed a liquid formula. Amino Acids. 48(6):1491-1508.
Yun, C., Yin, T., Shatzer, K., Burrin, D.G., Cui, L., Tu, Y., Hu, M. 2016. Determination of 7alpha-OH cholesterol by LC-MS/MS: Application in assessing the activity of CYP7A1 in cholestatic minipigs. Journal of Chromatography B. 1025:76-82.
Zhao, H., Yang, L., Baddour, J., Achreja, A., Bernard, V., Moss, T., Marini, J.C., Tudawe, T., Seviour, E.G., San Lucas, F., Alvarez, H., Gupta, S., Maiti, S.N., Cooper, L., Peehl, D., Ram, P.T., Maitra, A., Nagrath, D. 2016. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. eLife. 5:e10250.
Marjarin, R., Columbus, D.A., Suryawan, A., Hernandez-Garcia, A.D., Hoang, N., Fiorotto, M.L., Davis, T.A. 2015. Leucine supplementation of a chronically restricted protein and energy diet enhances mTOR pathway activation but not muscle protein synthesis in neonatal pigs. Amino Acids. 48(1):257-267.
Hanlon, S., Smith, C., Sauter, M., Burns, A. 2014. Intergrin-dependent neutrophil migration in the injured mouse cornea. Experimental Eye Research. 120:61-70.
Marini, J.C. 2016. Interrelationships between glutamine and citrulline metabolism. Current Opinion in Clinical Nutrition and Metabolic Care. 19(1):62-66.
Burrin, D.G. 2016. Trophic factors and regulation of gastrointestinal tract and liver development. In: Polin, R.A., Abman, S.H., and Fox, W.W. editors. Fetal and Neonatal Physiology, Section XIV Physiology of Gastrointestinal Tract in the Fetus and Neonate, 5th edition. Philadelphia PA: Elsevier Publishers. p. 853-858.
Ettayebi, K., Crawford, S.E., Murakami, K., Broughman, J.R., Karandikar, U., Tenge, V.R., Neill, F.H., Blutt, S.E., Zeng, X., Qu, L., Kou, B., Opekun, A.R., Burrin, D.G., Graham, D.Y., Ramani, S., Atmar, R.L., Estes, M.K. 2016. Replication of human noroviruses in stem cell-derived human enteroids. Science. doi: 10.1126/science.aaf5211.
Guthrie, G., Kulkarni, M., Vlaardingerbroek, H., Stoll, B., Ng, K., Martin, C., Belmont, J., Hadsell, D.L., Heird, W., Newgard, C., Olutoye, O., Van Goudoever, J., Lauridsen, C., Schuchman, E., Burrin, D.G. 2016. Multi-omic profiles of hepatic metabolism in TPN-fed preterm pigs. Journal of Lipid Research. 57(8):1-18. doi:10.1194/jlr.M069526.