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Research Project: Metabolic and Epigenetic Regulation of Nutritional Metabolism

Location: Children's Nutrition Research Center

2020 Annual Report

Our goal is to identify strategies to optimize the nutrition and health of infants and their development. We will: 1) determine the effect of enteral nutrition on the downstream signaling pathways and metabolism in various tissues; 2) determine if increased FGF19 availability controls the rate of growth, tissue protein synthesis and intestinal development; 3) determine if being born prematurely blunts protein and glucose metabolic responses to the feeding-induced rise in amino acids and insulin; 4) identify by which amino acids, regulate protein synthesis, degradation, and accretion and how these responses change with age; 5) identify the mechanisms that limit citrulline production; determine the basis for the greater citrulline production observed in females and determine the utilization of citrulline for endogenous arginine synthesis at different stages; 6) study the molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts; 7) determine the impact of maternal dietary protein level during lactation; 8) determine if vitamin D receptors in the brain are critical for glucose regulation; 9) determine if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A or B reduces the rates of gluconeogenesis; 10) study the role of the SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway; 11) alter DNA methylation in specific subpopulations of hypothalamic neurons and evaluate lifelong effects on energy metabolism, food intake, and physical activity; isolate specific neuronal (and potentially non-neuronal) hypothalamic cell types to evaluate cell type-specific alterations in DNA methylation in established models of nutritional programming; 12) find the causes of interindividual epigenetic variation and consequences for human energy balance; identify human metastable epialleles that predict risk of obesity; assess how DNA methylation at obesity-associated metastable epialleles is affected by maternal periconceptional nutrition; 13) determine the functional impact of folic acid supplementation and in intestinal carcinogenesis; 14) study the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone microarchitecture, bone biomarkers and endothelial function; 15) evaluate the effect of high dose vitamin D therapy on change in bone microarchitecture, restoration of bone biomarkers balance and endothelial function; and 16) determine anthropometry and body composition, total dietary energy intake, total energy expenditure, energy balance, biomarkers of cardiovascular health and early risk factors for Type 2 diabetes.

This research will be accomplished using a variety of models and scientific tools to simulate the human newborn and/or child. Researchers will use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. Additionally we will use various rodent models to test leptin's effect on gluconeogenesis that is independent of body weight, and will utilize in vitro experiments employing primary hepatocytes. Scientists will also integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. We will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function.

Progress Report
To review the progress made during the year, please refer to the following projects: 3092-51000-065-01S (Project #1), 3092-51000-065-02S (Project #2), 3092-51000-065-03S (Project #3) and 3092-51000-065-04S (Project #4).

1. Prematurity blunts the synthesis of muscle proteins after a meal. Worldwide, approximately 15 million infants are born preterm and these infants typically have a lower lean mass than those born full term. The lower lean mass in premature infants may contribute to their poorer short- and long-term health outcomes. Using the neonatal piglet as a model for the human infant, researchers in Houston, Texas, conducted a study to determine if preterm birth alters the intracellular mechanisms that regulate muscle growth in response to feeding. We showed that the synthesis of proteins in muscle after a meal was lower in preterms than those born at term, leading to a reduction in growth. This reduced response in the preterms can be attributed to a blunting of the activation of the intracellular signaling pathways in muscle that are regulated by amino acids and insulin in the blood. These animal studies provide the mechanisms that underlie the reduced lean growth in premature births and may provide relevance for the bedside care of preterm infants.

2. New generation lipid emulsions prevent liver disease. In the U.S., the main lipid emulsion approved for use in total parenteral nutrition (TPN) for preterm infants is based on soybean oil, called Intralipid. Studies in preterm babies and our studies in preterm piglets have shown that long-term infusion of soybean emulsions leads to a life-threatening condition known as parenteral nutrition-associated liver disease (PNALD). Researchers in Houston, Texas, tested two new lipid emulsions in premature, newborn piglets. One group received the new emulsion containing four different fats, called SMOF, and a second group (EXP) got a similar emulsion, but with enriched levels of key omega-fatty acids that are important for immune function. Our results showed that the SMOF and EXP emulsions prevented PNALD when compared to a control group given Intralipid. We also found that these new emulsions maintained the normal flow of bile into the gut and this led to marked changes in the gut bacterial population. These findings confirm previous work and show that new generation lipid emulsions prevent liver disease and that the underlying explanation may be related to changes in the bacteria in the gut.

3. Resources for pediatricians who provide care for obese children. When caring for obese children, pediatric health care providers must be able to gather information on diet, sleep, TV time, exercise, family history, as well as other items during a short visit and offer recommendations. There are few concise resources to help providers gather and evaluate information; thus, researchers at Houston, Texas, reviewed the literature for pediatric obesity and published a concise curation of resources for pediatric providers to aid families with information on nutrition, time-constraint strategies, and harmful eating behaviors. This work will be useful to all pediatric healthcare providers who counsel families with obese children.

4. Vitamin D enhances insulin action in brain cells. Vitamin D is associated with type 2 diabetes, but mechanisms understanding why are not clear. Researchers in Houston, Texas, previously showed that the brain may be a key site for vitamin D action to regulate blood sugar levels. New research shows that in brain cells, vitamin D increases the ability of insulin to act within these cells. Additionally, this new research shows that a key insulin pathway, the PI3K pathway, was needed in order for vitamin D to have both rapid and long-acting effects in brain cells. This is significant because it gives further evidence of how vitamin D may act in the brain to regulate blood sugar levels and demonstrates that the vitamin D and insulin pathways are interdependent in the brain.

5. Impaired suppression of glucose production in lean type 2 diabetic condition. Most investigations about type 2 diabetes have focused on the obese population; however, there is a distinct sub-population of type 2 diabetes patients who are lean with normal body mass index. It is not known if glucose production by the liver is differently affected in these individuals. Scientists in Houston, Texas, using a lean type 2 diabetes rat model, demonstrated that glucose production from the liver did not decrease appropriately after animals had eaten. These findings provide insights for future research about how to achieve better blood glucose control among this distinct sub-population of type 2 diabetes patients who are lean with normal body mass index.

6. Metabolic abnormalities in children, adolescents and young adults with Barth syndrome. Barth syndrome is a rare metabolic and neuromuscular disorder that occurs primarily in males with mortality frequently occurring during infancy and adolescence due to factors associated with the heart, immune system, muscles, and overall growth. It is not known if fatty acid and glucose metabolism is altered during this condition in humans. Researchers in Houston, Texas, demonstrated that fat oxidation was severely blunted during exercise in children, and an inability to increase fat metabolism during moderate physical activity is partially compensated by elevations in glucose metabolism. The data from this study suggests that abnormalities in glucose and fat metabolism contribute to the Barth syndrome condition and this research provides insights and potential nutritional interventions for the treatment of this condition.

7. Blood sugar pattern can inform risk for diabetes in children. It is important to identify children who are at risk for diabetes as early as possible, as some children do not receive a diagnosis until their symptoms are severe. A means to determine diabetes risk is to measure one's blood sugar (glucose) after consuming a sugary drink, and how quickly the blood sugar level rises. Researchers in Houston, Texas, along with collaborators from the University of Pittsburgh investigated whether the time for glucose to reach a peak after a sugary drink is associated with levels of insulin, a hormone that is important to keep the blood sugars normal. Individuals with a "late-peak" in blood sugar levels had lower insulin production and were less responsive to insulin. These findings indicate that examining how quickly the sugar rises after a sugary drink can inform pediatricians about a child's risk for diabetes and provide for an early intervention.

Review Publications
Suryawan, A.A., Rudar, M., Fiorotto, M.L., Davis, T.A. 2020. Differential regulation of mTORC1 activation by leucine and beta-hydroxy-beta-methylbutyrate in skeletal muscle of neonatal pigs. Journal of Applied Physiology. 128(2):286-295.
Ahnfeldt, A., Baek, O., Hui, Y., Nielsen, C., Obelitz-Ryom, K., Busk-Anderson, T., Ruge, A., Holst, J., Rudloff, S., Burrin, D.G., Nguyen, D., Nielsen, D., Zachariassen, G., Bering, S., Thymann, T., Sangild, P. 2020. Nutrient restriction has limited short-term effects on gut, immunity, and brain development in preterm pigs. Journal of Nutrition.
Blesson, C., Schutt, A., Chacko, S., Marini, J.C., Mathew, P.R., Tanchico, D., Balakrishnan, M., Yallampalli, C. 2019. Sex dependent dysregulation of hepatic glucose production in lean type 2 diabetic rats. Frontiers in Endocrinology. 10:538.
Nielsen, C., Hui, Y., Nguyen, D., Ahnfeldt, A., Burrin, D.G., Hartmann, B., Heckmann, A., Sangild, P., Thymann, T., Berinf, S. 2020. Alpha-lactalbumin enriched whey protein concentrate to improve gut, immunity and brain development in preterm pigs. Nutrients. 12(1):245.
Mohammad, M., Didelija, I., Wang, X., Stoll, B., Burrin, D.G., Marini, J. 2019. Developmental changes in the utilization of citrulline by neonatal pigs. American Journal of Physiology - Renal Physiology.
Hernandez, G.V., Smith, V.A., Melynk, M., Burd, M.A., Sprayberry, K.A., Edwards, M.S., Peterson, D.G., Bennet, D.C., Fanter, R.K., Columbus, D.A., Steibel, J., Glanz, H., Immoos, C., Rice, M.S., Santiago-Rodriguez, T.M., Blank, J.M., Vanderkelen, J.J., Kitts, C.L., Piccolo, B.D., La Frano, M.R., Burrin, D.G., Maj, M., Manjarin, R. 2020. Dysregulated FXR-FGF19 signaling and choline metabolism is associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH. American Journal of Physiology - Gastrointestinal and Liver Physiology. 318(3):G582-G609.
Smith, V., Jiang, Y., Thymann, T., Sangild, P., Maj, M., Manjarin, R., Burrin, D.G. 2020. Rapid postnatal upregulation of intestinal FXR-FGF19 signalling in premature pigs. Journal of Pediatric Gastroenterology and Nutrition.
Naberhuis, J.K., Suryawan, A., Nguyen, H.V., Hernandez-Garcia, A., Cruz, S.M., Lau, P.E., Olutoye, O.O., Stoll, B., Burrin, D.G., Fiorotto, M.L., Davis, T.A. 2019. Prematurity blunts the feeding-induced stimulation of translation initiation signaling and protein synthesis in muscle of neonatal piglets. American Journal of Physiology.
Burrin, D.G., Sangild, P., Stoll, B., Thymann, T., Buddington, R., Marini, J., Olutoye, O., Shulman, R. 2020. Translational advances in pediatric nutrition and gastroenterology: New insights from pig models. Annual Review of Animal Biosciences. 8(321):354.
Zachery, M., Sisley, S. 2020. The pediatric obesity encounter: Literature and resources to help with 4 common issues. Current Nutrition Reports. 9:94–100.
The Cancer Research UK - Ludwig Cancer Research Nutrition and Cancer Prevention Collaborative Group. 2019. Current opportunities to catalyze research in nutrition and cancer prevention - An interdisciplinary perspective. BioMed Central (BMC) Medicine. 17:148.
Li, G., Petkova, T.D., Laritsky, E., Kessler, N., Baker, M.S., Zhu, S., Waterland, R.A. 2019. Early postnatal overnutrition accelerates aging-associated epigenetic drift in pancreatic islets. Environmental Epigenetics. 5(3):dvz015.
Teixeira, S., Harrison, K., Uzodike, M., Rajapakshe, K., Coarfa, C., He, Y., Xu, Y., Sisley, S. 2020. Vitamin D actions in neurons require the PI3K pathway for both enhancing insulin signaling and rapid depolarizing effects. The Journal of Steroid Biochemistry and Molecular Biology. 200:105690.
Zang, T., Liu, J., Tong, Q., Lin, L. 2020. SIRT3 acts as a positive autophagy regulator to promote lipid mobilization in adipocytes via activating AMPK. International Journal of Molecular Sciences. 21(2):372.
Xin, L., Yang, L., Mao, Z., Pan, X., Zhao, Y., Gu, X., Eckel-Mahan, K., Zuo, Z., Tong, Q., Hartig, S.M., Cheng, X., Du, G., Moore, D.D., Bellen, H.J., Sesaki, H., Sun, K. 2020. Novel role of dynamin-related-protein 1 in dynamics of ER-lipid droplets in adipose tissue. Federation of American Societies for Experimental Biology Conference.
Horne, V., Bielamowicz, K., Nguyen, J., Hilsenbeck, S., Holly, L., Sonabend, R., Wood, A., Okcu, F., Sisley, S. 2020. Methylphenidate improves weight control in childhood brain tumor survivors with hypothalamic obesity. Pediatric Blood and Cancer. e28379.
Kim, J.Y., Tfayli, H., Bacha, F., Lee, S., Michaliszyn, S.F., Yousuf, S., Gebara, N., Arslanian, S. 2019. B-cell function, incretin response, and insulin sensitivity of glucose and fat metabolism in obese youth: Relationship of OGTT-time-to-glucose-peak. Pediatric Diabetes. 21:18-27.
Iqbal, N.T., Syed, S., Sadiq, K., Khan, M.N., Iqbal, J., Ma, J.Z., Umrani, F., Ahmed, S., Maier, E.A., Denson, L.A., Haberman, Y., McNeal, M.M., Setchell, K.D., Zhao, X., Qureshi, S., Shen, L., Moskaluk, C.A., Liu, T., Yilmaz, O., Brown, D.E., Barratt, M.J., Kung, V.L., Gordon, J.I., Moore, S.R., Ali, S.A. 2019. Study of environmental enteropathy and malnutrition (SEEM) in Pakistan: Protocols for biopsy based biomarker discovery and validation. BMC Pediatrics. 19:247.
Call, L., Molina, T., Stoll, B., Guthrie, G., Chacko, S., Plat, J., Robinson, J., Lin, S., Vonderohe, C., Mohammad, M., Kunichoff, D., Cruz, S., Lau, P., Premkumar, M., Nielsen, J., Fang, Z., Olutoye, O., Thymann, T., Britton, R., Sanglid, P., Burrin, D.G. 2020. Parenteral lipids shape gut bile acid pools and microbiota profiles in the prevention of cholestasis in preterm pigs. Journal of Lipid Research.
Rudar, M., Columbus, D.A., Steinhoff-Wagner, J., Suryawan, A., Nguyen, H.V., Fleischmann, R., Davis, T.A., Fiorotto, M.L. 2020. Leucine supplementation does not restore diminished skeletal muscle satellite cell abundance and myonuclear accretion when protein intake is limiting in neonatal pigs. Journal of Nutrition. 150(1):22-30.
Shah, V.N., Bailey, R., Wu, M., Foster, N.C., Pop-Busui, R., Katz, M., Crandall, J., Bacha, F., Nadeau, K., Libman, I., Hiers, P., Mizokami-Stout, K., Dimeglio, L.A., Sherr, J., Pratley, R., Agarwal, S., Snell-Bergeon, J., Cengiz, E., Polsky, S., Mehta, S.N. 2020. Risk factors for cardiovascular disease (CVD) in adults with type 1 diabetes: Findings from prospective real-life T1D Exchange Registry. Journal of Clinical Endocrinology and Metabolism. 105(5):e2032-e2038.
MacKay, H., Scott, C., Duryea, J.D., Baker, M.S., Laritsky, E., Elson, A.E., Garland, T., Fiorotto, M.L., Chen, R., Li, Y., Coarfa, C., Simerly, R.B., Waterland, R.A. 2019. DNA methylation in AgRP neurons regulates voluntary exercise behavior in mice. Nature Communications. 10:5364.
Astrup, A., Magkos, F., Bier, D.M., Brenna, J., De Oliveira Otto, M.C., Hill, J.O., King, J.C., Mente, A., Ordovas, J.M., Volek, J.S., Dphil, S., Krauss, R.M. 2020. Saturated fats and health: A reassessment and proposal for food-based recommendations: JACC state-of-the-art review. Journal of the American College of Cardiology.
Tryggestad, J.B., Shah, R.D., Braffett, B.H., Bacha, F., Gidding, S.S., Gubitosi-Klug, R.A., Shah, A.S., Urbina, E.M., Levitt Katz, L.E. 2020. Circulating adhesion molecules and associations with HbA1c, hypertension, nephropathy, and retinopathy in the treatment options for type 2 Diabetes in adolescent and youth study. Pediatric Diabetes.
Bacha, F., El Ghormli, L., Arslanian, S., Zeitler, P., Laffel, L.M., Levitt Katz, L.E., Gandica, R., Chang, N.T., Sprague, J.E., Macleish, S.A., The TODAY Study Group. 2019. Predictors of response to insulin therapy in youth with poorly controlled type 2 diabetes in the TODAY trial. Pediatric Diabetes. 20(7):871-879.
Guthrie, G.J., Stoll, B., Chako, S., Lauridsen, C., Plat, J., Burrin, D.G. 2019. Rifampicin, not vitamin E, suppresses parenteral nutrition-associated liver disease development through pregnane X receptor pathway in piglets. American Journal of Physiology - Gastrointestinal and Liver Physiology. 318:G41-G52.
Shah, A.S., El Ghomli, L., Vajravelu, M., Bacha, F., Farrell, R.M., Gidding, S.S., Levitt Katz, L.E., Tryggestad, J.B., White, N.H., Urbina, E.M. 2019. Heart rate variability and cardiac autonomic dysfunction: Prevalence, risk factors, and relationship to arterial stiffness in the treatment options for type 2 diabetes in adolescents and youth (TODAY) study. Diabetes Care. 42(11):2143-2150.
Liu, Z., Liu, H., He, J., Lin, P., Tong, Q., Yang, J. 2020. Myeloma cells shift osteoblastogenesis to adipogenesis by inhibiting the ubiquitin ligase MURF1 in mesenchymal stem cells. Science Signaling. 13(633):eaay8203.
Zhang, T., Liu, J., Shen, S., Tong, Q., Ma, X., Lin, L. 2020. SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity. Cell Death and Differentiation. 27:329-344.
Athanassaki, I., Lyons, S., Desalvo, D., Hendrix, K., Ebenezer, S., McCann-Crosby, B., Redondo, M., Chen, M., Uysal, S., Sisley, S. 2020. Diabetes curriculum for pediatric endocrine fellowship utilizing modified team-based learning. MedEdPORTAL. 16:10948.