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Research Project: Metabolic and Epigenetic Regulation of Nutritional Metabolism

Location: Children's Nutrition Research Center

2021 Annual Report

We will: 1)study the effect of enteral nutrition on the downstream signaling pathways and metabolism;2)study if increased FGF19 availability controls rate of growth, tissue protein synthesis and intestinal development;3)study 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 responses change with age;5)identify the mechanisms that limit citrulline production;6)study molecular mechanisms and functional significance of differences in gene expression identified in satellite cell-derived myoblasts;7)study the impact of maternal dietary protein level during lactation;8)study if vitamin D receptors in the brain are critical for glucose regulation;9)study if leptin is involved in the regulation of gluconeogenesis via the leptin receptor and if leptin agonist and small doses of hypoglycin-A/B reduces 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 PA;12)find the causes of interindividual epigenetic variation and consequences for human energy balance;13)study 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 and endothelial function; 15)study the effect of vitamin D therapy on change in bone and endothelial function;16)study anthropometry and body composition, total dietary energy intake, TEE, energy balance, biomarkers of CVD health and early risk factors for T2D;17)study the CNS circuit architecture and explore circuit complexities that regulate non-homeostatic feeding behaviors via environmental signals transduced by epigenetic mechanisms;18)study the tumorigenic effects of HFCS on a humanized colon tumor mouse model;19)study the effects of HFCS on the gut microbiota of a humanized colon tumor mouse model;20)study the role of HFCS-induced gut microbiota in CRC development; create multi-omic nutritional data share portal to resolve the unmet demand for an efficient access to the large volumes of heterogeneous multi-omic data across various research labs;21)integrate heterogeneous multi-omic datasets such as genetic (SNPs), transcriptomic, epigenetic, proteomic, metabolomic and microbiome to infer molecular network structures illustrating eating disorder dynamics;&22)decode genetic and epigenetic patterns of disordered eating using machine learning methods.

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. Studies will be conducted in mice that will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets. Researchers will also conduct a multi-omic integrative study to systematically decipher the molecular interplay of disordered eating and neuron specific brain circuits that control feeding behavior.

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 dampens the anabolic response to nutrition. Approximately 10% of all United States infants born annually (380,000) are preterm thus it is vital to conduct studies that seek to provide optimal nutrition for this group. The lean growth of preterm infants is typically lower than infants born at term and likely contributes to undesirable short-term and long-term health outcomes. Using the neonatal pig as a model for the human infant, researchers in Houston, Texas, determined the mechanisms by which preterm birth alters the response to nutritional growth. Our work showed that preterm birth impairs the ability of skeletal muscle to increase the synthesis of protein after a meal. These studies provide vital information on the mechanisms underpinning the reduced growth of lean muscle mass after birth in preterm infants and will aid in the development of nutritional therapies to improve lean growth.

2. Creation of a new mouse model to identify vitamin D receptors in the brain. Vitamin D acts in the brain to control blood sugar, but the exact mechanisms are not known. Typically, the first step in understanding how vitamin D acts would be to determine what types of neurons contain the vitamin D receptor. However, the available antibodies to identify vitamin D receptors do not work in the brain. Researchers in Houston, Texas, created a new mouse model which identifies vitamin D receptors in the mouse brain through a special fluorescent reporter. Researchers successfully validated that only those neurons containing the fluorescent reporter were activated by vitamin D. This new mouse model is important as it allows researchers to identify and manipulate neurons containing the vitamin D receptor. This is an important new tool which will aid researchers investigating the role of vitamin D in the brain and its impact on diabetes, Alzheimer's disease, obesity, and other brain-related disorders.

3. The effect of cardiorespiratory fitness and insulin resistance on bone health in Hispanic children. Obesity appears to have a negative impact on pediatric bone health, and insulin resistance may mediate this relationship. It was unclear if cardiorespiratory fitness has a protective effect on bone in obese children thus, researchers in Houston, Texas, found that lean body mass is the major determinant of bone mineral content and bone mineral density in pubertal Hispanic youth. Increased body fat and insulin resistance were negatively related to bone mineral content. Cardiorespiratory fitness contributed positively to bone mineral content and density. This suggests that greater cardiorespiratory fitness and higher lean mass may reduce the adverse effects of adiposity and insulin resistance on bone health in children. This supports the importance of promoting physical activity to prevent the negative impact of obesity on bone health in children.

4. Metabolic flexibility across the spectrum of glycemic regulation in youth. Metabolic flexibility refers to the ability to utilize different nutrients (fats and sugars) and to transition between them while fasting and after a meal. Impairment in metabolic flexibility can lead to metabolic disease. However, it is not clear whether metabolic flexibility is impaired in obese youth, or who is at risk. Therefore, researchers in Houston, Texas, found that adolescents with prediabetes and type 2 diabetes have a defect in metabolic flexibility. Individuals with prediabetes and type 2 diabetes can't change the use of fuels as easily as normal weight individuals or individuals with obesity but with normal sugar levels. This is related to their severe insulin resistance which impairs the appropriate use of available fuels. Additional studies are needed to investigate which changes in diet or physical activity could improve how the body utilizes these nutrients.

5. Insufficient sleep duration and quality may lead to increased weight gain in children. Multiple studies have found an association between short sleep duration and obesity in children and adolescents; however, the mechanisms underlying the relationship between sleep and the risk for obesity in children are unclear. One mechanism may be through changes in energy metabolism and physical activity. Researchers in Houston, Texas, investigated the relationship of various sleep parameters (sleep duration and quality) to energy metabolism and physical activity in children and adolescents aged 5-18 years. Researchers measured the child/adolescent's body composition, basal metabolic rate, and sleep and physical activity parameters during a school break. The scientists found that children and adolescents do not consistently meet the age-recommended sleep duration during school breaks. Importantly, shorter sleep duration was associated with lower basal metabolic rate which indicates that insufficient sleep duration and late sleep timing may lead to increased weight gain over time. This supports the importance of sleep hygiene with appropriate timing and adequate duration in promoting an active lifestyle and minimizing sedentary behaviors to prevent childhood obesity.

6. Insulin resistance affects the insulin regulation of glucose and triglyceride production. Insulin resistance is a condition when cells in muscles, fat, and the liver do not respond efficiently to insulin and are unable to easily take up glucose from circulation. In the liver, insulin suppresses glucose production and increases lipid synthesis in the presence of glucose. It is not clear as to what mechanisms insulin regulates glucose and triglyceride (a type of lipid) production in humans with various types of insulin resistance conditions. Scientists in Houston, Texas, demonstrated that glycerol and free fatty acid availability (two precursors to triglyceride synthesis) are increased in two different models of insulin resistance, one involving the insulin receptor (receptor-level) and one caused by defects in the pathway after the insulin receptor (postreceptor). In receptor-level insulin resistance, free fatty acid oxidation increased glucose production rather than triglyceride production. In contrast, free fatty acids contributed to both glucose and triglyceride production in postreceptor insulin resistance conditions. The findings from this research provides details about glucose and fat metabolism in these insulin resistance conditions and insights for future research to find effective treatments.

7. Using blood markers to determine weight status in individuals with type 1 diabetes. Researchers often struggle to get accurate height and weight measurements when conducting studies outside of medical facilities. These measurements are critical for determining a person's body mass index which is used to determine if an individual is overweight or obese. Most studies obtain blood draws and there are many hormones which circulate in the blood that relate to a person's weight status; whether these hormones would be an accurate reflection of weight status in an individual with type 1 diabetes was not known. Researchers at Houston, Texas, used existing samples from a multi-site trial comprised of individuals with type 1 diabetes to determine if there were any markers identified in blood that would reflect weight status. They found that leptin was a good marker for weight status in boys but not in girls; however, waist circumference was a good marker in girls, which may be easier to collect than height and weight. Overall, this data shows promise and further studies should be performed to identify possible biomarkers since, if successful, a blood biomarker would allow for many questions related to obesity to be asked in existing datasets of banked samples.

8. Leptin decreases fat synthesis in individuals with lipodystrophy. Lipodystrophy is a medical condition in which the body has abnormal distribution of fat and results in nonalcoholic fatty liver disease, the most common cause of chronic liver disease in the U.S. and is likely to become the leading cause of liver failure. It is not known if a leptin analog treatment in individuals with lipodystrophy would reduce fat synthesis in the liver. Scientists in Houston, Texas, demonstrated that six months of the leptin analog (metreleptin) treatment in very insulin-resistant people with lipodystrophy led to near normalization of fatty acid synthesis. Improvements in fat synthesis in the liver were associated with reductions in blood glucose and improved insulin sensitivity. These findings indicate that metreleptin treatment lowered liver fat accumulation (hepatic steatosis) and blood lipid levels and suggests that treatments targeting multiorgan insulin resistance may improve nonalcoholic fatty liver disease.

Review Publications
Redondo, M., Siller, A., Gu, X., Tosur, M., Bondy, M., Devaraj, S., Sisley, S. 2020. Sex differences in circulating leptin as a marker of adiposity in obese or overweight adolescents with type 1 diabetes. BMJ Open Diabetes Research & Care.
Yakah, W., Singh, P., Brown, J., Stoll, B., Burrin, D.G., Premkumar, M., Otu, H., Gu, X., Dillon, S., Liberman, T., Freedman, S., Martin, C. 2020. Parenteral lipid emulsions induce unique ileal fatty acid and metabolomic profiles but do not increase the risk of necrotizing enterocolitis in preterm pigs. American Journal of Physiology - Gastrointestinal and Liver Physiology.
Mohammad, M.A., Didelija, I.C., Marini, J.C. 2020. Arginase II plays a central role in the sexual dimorphism of arginine metabolism in C57BL/6 mice. Journal of Nutrition. 150(12):3133-3140.
Mohammad, M., Didelija, I., Stoll, B., Burrin, D.G., Marini, J. 2020. Modeling age-dependent developmental changes in the expression of genes involved in citrulline synthesis using pig enteroids. Physiological Reports. 8(21):e14565.
Yakah, W., Ramiro-Cortijo, D., Singh, P., Brown, J., Stoll, B., Kulkarni, M., Oosterloo, B., Burrin, D.G., Maddipati, K., Fichorova, R., Freedman, S., Martin, C. 2021. Parenteral fish-oil containing lipid emulsions limit initial lipopolysaccharide-induced host immune responses in preterm pigs . Nutrients. 13(1):25.
Cade, T.W., Bohnert, K.L., Bittel, A.J., Chacko, S.J., Patterson, B.W., Pacak, C.A., Byrne, B.J., Vernon, H.J., Reeds, D.N. 2020. Arginine kinetics are altered in a pilot sample of adolescents and young adults with Barth syndrome. Molecular Genetics and Metabolism. 25:100675.
Ettayebi, K., Tenge, V., Cortes-Penfield, N., Crawford, S., Neill, F., Zeng, X., Yo, X., Ayyar, V., Burrin, D.G., Ramani, S., Atmar, R., Estes, M. 2021. New insights and enhanced human norovirus cultivation in human intestinal enteroids . American Society for Microbiology. 6(1):e01136-20.
Liu, H., He, Y., Beck, J., Da Silva Teixeira, S., Harrison, K., Xu, Y., Sisley, S. 2020. Defining vitamin D receptor expression in the brain using a novel VDRCre mouse. Journal of Comparative Neurology.
Guthrie, G., Burrin, D.G. 2021. Impact of parenteral lipid emulsion components on cholestatic liver disease in neonates. Nutrients. 13(2):508.
Leroy, J.L., Frongillo, E.A., Dewan, P., Black, M.M., Waterland, R.A. 2020. Can children catch up from the consequences of undernourishment? Evidence from child linear growth, developmental epigenetics, and brain and neurocognitive development. Advances in Nutrition. 11(4):1032-1041.
Burrin, D.G., Marini, J., Premkumar, M., Stoll, B., Sangild, P. 2021. Advancements in research on necrotizing enterocolitis pathogenesis and prevention using pigs. In: Hackam, D.J. editor. Necrotizing Enterocolitis: Pathogenesis, Diagnosis and Treatment. 1st edition. Boca Raton, FL: CRC Press. p.220-232.
Mohammad, M., Didelija, I., Stoll, B., Nguyen, T., Marini, J. 2021. Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs. American Journal of Physiology. 320(3):E641-E652.
Kim, J.Y., Tfayli, H., Bacha, F., Arslanian, S. 2021. The shape of the oral glucose tolerance test-glucose response curve in islet cell antibody-positive vs. -negative obese youth clinically diagnosed with type 2 diabetes. Journal of Obesity.
Deng, F., Zhou, H., Lin, Y., Heim, J.A., Shen, L., Li, Y., Zhang, L. 2021. Predict multicategory causes of death in lung cancer patients using clinicopathologic factors. Computers in Biology and Medicine. 129:104161.
Kim, J., Tfayli, H., Bacha, F., Lee, S., Gebara, N., Arslanian, S. 2020. B-cell impairment and clinically meaningful alterations in glycemia in obese youth across the glucose tolerance spectrum. Metabolism: Clinical and Experimental. 112:154346.
Robinson, S.L., Zeng, X., Guan, W., Sundaram, R., Mendola, P., Putkick, D.L., Waterland, R.A., Ganasekara, C., Kannan, K., Gao, C., Bell, E., Yeung, E.H. 2021. Perfluorooctanoic acid (PFOA) or perfluorooctane sulfonate (PFOS) and DNA methylation in newborn dried blood spots in the upstate KIDS cohort. Environmental Research. 194:110668.
Scott, A.C., Duryea, J.D., MacKay, H., Baker, M.S., Laritsky, E., Gunasekara, C.J., Coarfa, C., Waterland, R.A. 2020. Identification of cell type-specific methylation signals in bulk whole genome bisulfite sequencing data. Genome Biology. 21(1):156.
Mukherjee, S., Mo, J., Paolella, L.M., Perry, C.E., Toth, J., Hugo, M.M., Chu, Q., Tong, Q., Chellappa, K., Baur, J.A. 2021. SIRT3 is required for liver regeneration but not for the beneficial effect of nicotinamide riboside. Journal of Clinical Immunology Insights (JCI Insights). 6(7):E147193.
Shen, H., Holliday, M., Sheikh-Hamad, D., Li, Q., Tong, Q., David Hamad, C., Pan, J.S. 2021. Sirtuin-3 mediates sex differences in kidney ischemia-reperfusion injury. Translational Research.
Deng, F., Shen, L., Wang, H., Zhang, L. 2020. Classify multicategory outcome in patients with lung adenocarcinoma using clinical, transcriptomic and clinico-transcriptomic data: Machine learning versus multinomial models. American Journal of Cancer Research. 10(12):4624-4639.
Al-Gadi, I., Sisley, S. 2021. Case-based curriculum for pediatric residents in diabetes fundamentals. MedEdPORTAL. 17:11157.
Bailey, R.L., Ard, J.D., Davis, T.A., Naimi, T.S., Schneeman, B.O., Stang, J.S., Dewey, K.G., Donovan, S.M., Novotny, R., Snetselaar, L.G. 2021. A proposed framework for identifying nutrients and food components of public health relevance in the Dietary Guidelines for Americans. Journal of Nutrition. 151(5):1197-1204.
El-Kadi, S.W., Boutry-Regard, C., Suryawan, A., Nguyen, H.V., Kimball, S.R., Fiorotto, M.L., Davis, T.A. 2020. Intermittent bolus feeding enhances organ growth more than continuous feeding in a neonatal piglet model. Current Developments in Nutrition. 4(12):nzaa170.
Bacha, F., Bartz, S.K., Puyau, M., Adolph, A., Sharma, S. 2021. Metabolic flexibility across the spectrum of glycemic regulation in youth. Journal of Clinical Investigation. 6(4):e146000.
Jindal, I., Puyau, M., Adolph, A., Butte, N., Musaad, S., Bacha, F. 2020. The relationship of sleep duration and quality to energy expenditure and physical activity in children. Pediatric Obesity. e12751.
Baykal, A.P., Parks, E.J., Shamburek, R., Syed-Abdul, M.M., Chacko, S., Cochran, E., Startzell, M., Gharib, A.M., Ouwerkerk, R., Abd-Elmoniem, K.Z., Walter, P.J., Muniyappa, R., Chung, S.T., Brown, R.J. 2020. Leptin decreases de novo lipogenesis in patients with lipodystrophy. Journal of Clinical Investigation. 5(14):e137180.
Maj, M., Harbottle, B., Thomas, P., Hernandez, G., Smith, V., Edwards, M., Fanter, R., Glanz, H., Immoos, C., Burrin, D.G., Santiago-Rodriguez, T., La Franco, M., Manjarin, R. 2021. Consumption of high-fructose corn syrup compared with sucrose promotes adiposity and increased triglyceridemia but comparable NAFLD severity in juvenile Iberian pigs . Journal of Nutrition. 151(5):1139-1149.
Guthrie, G., Stoll, B., Chacko, S., Mohammad, M., Style, C., Verla, M., Olutoye, O., Schady, D., Lauridsen, C., Tataryn, N., Burrin, D.G. 2021. Depletion and enrichment of phytosterols in soybean oil lipid emulsions directly associate with serum markers of cholestasis in preterm PN-fed pigs. Journal of Parenteral and Enteral Nutrition.
Kumar, P., Liu, C., Suliburk, J.W., Minard, C.G., Muthupillai, R., Chacko, S., Hsu, J.W., Jahoor, F., Sekhar, R.V. 2020. Supplementing glycine and n-acetylcysteine (GlyNAC) in aging HIV patients improves oxidative stress, mitochondrial dysfunction, inflammation, endothelial dysfunction, insulin resistance, genotoxicity, strength, and cognition: Results of an open-label clinical trial. Biomedicines. 8(10):390.
Zeltser, N., Meyer, I., Hernandez, G., Trahan, M., Fanter, R., Abo-Ismail, M., Glanz, H., Strand, C., Burrin, D.G., La Frano, M., Manjarin, R., Maj, M. 2020. Neurodegeneration in juvenile Iberian pigs with diet-induced nonalcoholic fatty liver disease. American Journal of Physiology - Endocrinology and Metabolism. 319(3):E592-E606.
Suryawan, A., El-Kadi, S.W., Nguyen, H.V., Fiorotto, M.L., Davis, T.A. 2021. Intermittent bolus compared with continuous feeding enhances insulin and amino acid signaling to translation initiation in skeletal muscle of neonatal pigs. Journal of Nutrition.
Rudar, M., Naberhuis, J.K., Suryawan, A., Nguyen, H.V., Stoll, B., Style, C.C., Verla, M.A., Olutoye, O.O., Burrin, D.G., Fiorotto, M.L. 2021. Prematurity blunts the insulin- and amino acid-induced stimulation of translation initiation and protein synthesis in skeletal muscle of neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 320(3):E551–E565.
Sorkin, J.D., Manary, M., Smeets, P.A., MacFarlane, A.J., Astrup, A., Duggan, C.P., Hogans, B.B., Odle, J., Davis, T.A., Tucker, K.L. 2021. A guide for authors and readers of the American Society for Nutrition Journals on the proper use of P values and strategies that promote transparency and improve research reproducibility. American Journal of Clinical Nutrition.
Gooding, H.C., Gidding, S.S., Moran, A.E., Redmond, N., Allen, N.B., Bacha, F., Burns, T.L., Catov, J.M., Grandner, M.A., Mullan Harris, K., Johnson, H.M., Kiernan, M., Lewis, T.T., Matthews, K.A., Monaghan, M., Robinson, J.G., Tate, D., Bibbins-Domingo, K., Spring, B. 2020. Challenges and opportunities for the prevention and treatment of cardiovascular disease among young adults: Report from a National Heart, Lung, and Blood Institute working group. Journal of the American Heart Association. 9(19):e016115.
Sekizkardes, H., Chung, S.T., Chacko, S., Haymond, M.W., Startzell, M., Walter, M., Walter, P.J., Lightbourne, M., Brown, R.J. 2020. Free fatty acid processing diverges in human pathologic insulin resistance conditions. Journal of Clinical Investigation. 130(7):3592-3602.
Momin, S.R., Senn, M.K., Buckley, S., Buist, N.R., Gandhi, M., Hair, A.B., Hughes, S.O., Hodges, K.R., Lange, W.C., Papaioannou, M.A., Phan, M., Waterland, R.A., Wood, A.C. 2020. Rationale and design of the Baylor Infant Twin Study (BITS) - A study assessing obesity-related risk factors from infancy. Obesity Science & Practice.