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United States Department of Agriculture

Agricultural Research Service

Related Topics

Research Project: MOLECULAR, CELLULAR, AND REGULATORY ASPECTS OF OBESITY DEVELOPMENT IN CHILDREN

Location: Children's Nutrition Research Center

2011 Annual Report


1a. Objectives (from AD-416)
1) determine role of circadian clock in regulation of food intake and interaction between diet composition and circadian rhythms of food intake on body weight control during post-weaning and adult life; determine specific role of central and peripheral clocks, as well as circadian output pathways in maintaining homeostasis of food intake; (2-3 removed; SYs left); 4) investigate impact of prematurity on GI and metabolic response to perinatal nutrition; 5) compare impact of continuous vs. intermittent bolus delivery of nutrients provided enterally or parenterally on protein synthesis and accretion in neonatal models and identify intracellular signaling mechanism involved; 8) investigate changes of SIRT3 gene expression in the liver, and study effects of SIRT3 expression on hepatic metabolism, oxidative stress, and fat deposition; 9) determine role of protein kinase C interacting cousin of thioredoxin in insulin-mediated growth, macronutrient metabolism, and insulin resistance in the liver; 10) define action of glucagon-like peptide-2 (GLP-2) receptor on food intake and inter-organ macronutrient flux; 11) study ghrelin peptide expression profile under different diet regimes; 12) conduct mechanistic analyses of differences in metabolic profile between WT and null mice; 13) confirm predicted lipotropic effects of lecithin, choline and betaine in high-fat-fed mouse models of the metabolic syndrome; 14) test impact of liver specific LRH-1 knockout on the lipotropic effects of lecithin, choline and betaine in high-fat-fed mouse models of the metabolic syndrome; 15)identify genes that show epigenetic dysregulation in obesity; 16) determine if methylation and expression of specific genes in hypothalamus and/or adipose tissue differ between lean and obese animals and determine if maternal obesity and/or nutrition before and during pregnancy persistently alters epigenetic regulation in offspring; 17) determine if maternal obesity and/or nutrition before and during pregnancy persistently alters epigenetic regulation in offspring hypothalamus or adipose tissue; 18) identify placental epigenetic mechanisms that affect fetal nutrition, growth and development; 19) determine how programming of glucose intolerance, obesity, and the epigenetic dysregulation of skeletal muscle-growth in mice is affected by maternal diet during development; 20) determine if epigenetic programming and reprogramming contribute to lineage-specific patterns of gene expression; 21) develop targested knock-in mouse model to determine if nutrients can modulate hypermethylation, epigenetic silencing and increase susceptibility to disease; 22) evaluate leukocyte patterns, gene expression profiles, and inflammatory mediators in adipose tissue under influence of diatary manipulation that leads to obesity.


1b. Approach (from AD-416)
The research will be accomplished using a variety of animal models and scientific tools to simulate the human newborn and/or child. Animal models will be used to understand the central and peripheral circadian clock mechanisms that influence eating behavior, metabolism, and energy balance. Newborm animal models will be used to examine the effect of chronic parenteral nutrition during the neonatal period on glucose tolerance, insulin sensitivity, and body composition during late infancy and adolescence. Researchers will investigate the effects of intermittent bolus feeding versus continuous feeding, delivered either enterally or parenterally, on protein synthesis in neonatal animal models. This will allow our team to determine the long-term impact of these feeding modalities on growth and body composition. Various models will be placed on obesigenic diets at 5-6 weeks of age and evaluated at 7 days, 5 weeks, and 6 months to define a blood leukocyte expression profile at these time points. Children's Nutrition Research Center scientists will also characterize the functions of intracellular systems in the liver and their influences on the onset of fatty liver disease and glucose homeostasis. Additional investigation will occur on the intracellular signaling pathways of GLP-2 and their metabolic effects on food intake, energy expenditure, and glucose homeostasis. Various mouse models, and a human model of epigenetic dysregulation compromising placental development, will be used to test if maternal obesity and fetal nutrition during development affects the establishment of gene-specific DNA methylation patterns in the developing fetus, which would cause permanent changes in gene expression, metabolism, food intake regulation, and body weight. Additionally we will investigate the mechanisms regulating DNA methylation during development, and characterize their involvement in nutritional programming during critical ontogenic periods. We will characterize the role of ghrelin and its receptor in nutritional regulation of energy and glucose homeostasis.


3. Progress Report
Proj. 1 We investigated the molecular mechanism of circadian control of leptin expression in the fat tissue and bile acid synthesis, metabolism, and signaling in the liver and found that the circadian clock is involved in regulating leptin expression and bile acid synthesis at the transcriptional level, and disruption of circadian rhythm disrupts the balance of leptin interaction with brain centers controlling energy balance. Proj. 2 We showed in models that parenteral vs. enteral nutrition results in poor metabolic condition marked by increased fat, glucose intolerance, and inflammatory stress. We showed that intermittent bolus feeding stimulates protein synthesis by activating the signaling proteins that regulate protein synthesis, but the time course varies among tissues. Proj. 3 We conducted gene expression analysis on blood, liver, and fat tissues from mice fed a high or a low fat diet. We studied mice with a CD11c deficiency to see if CD11c was important to the inflammation that occurs in the fat tissues of the obese mice. Proj. 4 We examined the effects of nutritional or hormone changes on SIRT3 expression in cultured hepatocytes, the primary cells of the liver. We generated transgenic mice targeting the specific gene Grx3, that will be used as a genetic tool to delete the Grx3 gene in specific tissues. We conducted studies to determine the physiological role of GLP-2, a gut hormone, in the central nervous system in the control of blood glucose; we deleted GLP-2R in hypothalamic neurons and demonstrated that GLP-2R deletion in these neurons increases glucose production in the liver by decreasing insulin responsiveness, suggesting that brain GLP-2R activation is important for maintaining blood glucose levels. We have generated a new 5-HT2CR floxed mouse model. In parallel, we used mouse models with estrogen receptor-alpha (a receptor that is activated by the sex hormone estrogen) deleted in the central nervous system. Proj. 5 We studied if early postnatal over nutrition by suckling in small litters induces permanent increases in weight and fatness, relative to mice suckled in normal size control litters. We used a genome-wide method (MSAM) to screen for persistent changes in hypothalamic DNA methylation in these models, but no major differences were detected. We profiled DNA methylation across the genome to compare androgenetic hydatidiform, ovarian teratomas, and normal placentas. We studied the function of NLRP7 to confirm in various cell lines that this protein interacts with CTCF and YY1, two proteins important in the regulation of imprinting, as well as with NPM1, a protein that we found to bind to NRLP7. We performed gene expression profiling using RNA from liver and muscle of mice born to mothers fed a low-protein diet. We found many expression changes in liver at age 1 yr. We completed MSAM to compare methylation in human embryonic stem cells before and after induced differentiation and identified 3% of genomic regions that are targets for programmed methylation. We are developing a model to understand the signals that determine locus-specific DNA methylation in vivo.


4. Accomplishments


Review Publications
Davis, T.A., Suryawan, A., Orellana, R.A., Fiorotto, M.L., Burrin, D.G. 2010. Amino acids and insulin are regulators of muscle protein synthesis in neonatal pigs. Animal. 4(11):1790-1796.

Taylor-Edwards, C.C., Burrin, D.G., Matthews, J.C., McLeod, K.R., Holst, J.J., Harmon, D.L. 2010. Expression of mRNA for proglucagon and glucagon-like peptide-2(GLP-2) receptor in the ruminant gastrointestinal tract and the influence of energy intake. Domestic Animal Endocrinology. 39:181-193.

Ma, K., Xiao, R., Tseng, H., Shan, L., Fu, L., Moore, D.D. 2009. Circadian dysregulation disrupts bile acid homeostasis. PLoS One. 4(8): e6843.

Yang, Y., Cimen, H., Han, M., Shi, T., Deng, J., Koc, H., Palacios, O.M., Montier, L., Bai, Y., Tong, Q., Koc, E.C. 2010. NAD (+)- dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of the ribosomal protein MRPL10. Journal of Biological Chemistry. 285(10):7417-7429.

Waterland, R., Kellermayer, R., Rached, M., Tatevian, N., Gomes, M.V., Zhang, J., Zhang, L., Chakravarty, A., Zhu, W., Laritsky, E., Zhang, W., Wang, X., Shen, L. 2009. Epigenomic profiling indicates a role for DNA methylation in early postnatal liver development. Human Molecular Genetics. 18(16):3026-3038.

Waterland, R.A. 2009. Early environmental effects on epigenetic regulation in humans. Epigenetics. 4(8):523-525.

Reynolds, L.P., Ireland, J.J., Caton, J.S., Bauman, D.E., Davis, T.A. 2009. Commentary on domestic animals in agricultural and biomedical research: An endangered enterprise. Journal of Nutrition. 139(3):427-428.

Lee, S., Donehower, L., Herron, A.J., Moore, D.D., Fu, L. 2010. Disrupting circadian homeostasis of sympathetic signaling promotes tumor development in mice. Available: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0010995

Waterland, R.A., Kellermayer, R., Laritsky, E., Rayco-Solon, P., Harris, R.A., Travisano, M., Zhang, W., Torskaya, M.S., Zhang, J., Shen, L., Manary, M.J., Prentice, A.M. 2010. Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles. PLoS Genetics. 6(12):e1001252.

Harris, R.A., Wang, T., Coarfa, C., Nagarajan, R.P., Hong, C., Downey, S.L., Johnson, B.E., Fouse, S.D., Delaney, A., Zhao, Y., Olshen, A., Ballinger, T., Zhou, X., Forsberg, K.J., Gu, J., Echipare, L., O'Geen, H., Lister, R., Pelizzola, M., Xi, Y., Epstein, C.B., Bernstein, B.E., Hawkins, R., Ren, B., Chung, W., Gu, H., Bock, C., Gnirke, A., Zhang, M.Q., Haussler, D., Ecker, J.R., Li, W., Farnham, P.J., Waterland, R., Alexander, M., Marra, M.A., Hirst, M., Milosavljevic, A., Costello, J.F. 2010. Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. Nature Biotechnology. 28:1097-1105.

Qu, Y., Wang, J., Ray, P.S., Guo, H., Huang, P., Shin-Sim, M., Bukoye, B.A., Liu, B., Lee, A.V., Lin, X., Huang, P., Martens, J.W., Giuliano, A.E., Zhang, N., Ning-Hui, C., Cui, X. 2011. Thioredoxin-like 2 regulates human cancer cell growth and metastasis via redox homeostasis and NF-kB signaling. Journal of Clinical Investigation. 121(1):212-225.

Cheng, N.H., Liu, J., Liu, X., Wu, Q., Thompson, S.M., Lin, J., Chang, J., Whitham, S.A., Park, S., Cohen, J.D., Hirschi, K.D. 2011. Arabidopsis monothiol glutaredoxin, AtGRXS17, is critical for temperature-dependent postembryonic growth and development via modulating auxin response. Journal of Biological Chemistry. 286(23):20398-20406.

Wilson, F.A., Suryawan, A., Orellana, R.A., Gazzaneo, M.C., Nguyen, H.V., Davis, T.A. 2010. Differential effects of long-term leucine infusion on tissue protein synthesis in neonatal pigs. Amino Acids. 40(1):157-165.

Escobar, J., Frank, J.W., Suryawan, A., Nguyen, H.V., Van Horn, C.G., Hutson, S.M., Davis, T.A. 2010. Leucine and alpha-Ketoisocaproic acid, but not norleucine, stimulate skeletal muscle protein synthesis in neonatal pigs. Journal of Nutrition. 140(8):1418-1424.

Cimen, H., Han, M., Yang, Y., Tong, Q., Koc, H., Koc, E.C. 2010. Regulation of succinate dehydrogenase activity by SIRT3 in mammalian mitochondria. Biochemistry. 49(2):304-311.

Mcallister, E.J., Dhurandhar, N.V., Keith, S.W., Aronne, L.J., Barger, J., Baskin, M., Benca, R.N., Biggio, J., Boggiano, M.M., Eisenmann, J.C., Elobeid, M., Fontaine, K.R., Gluckman, P., Hanlon, E.C., Katzmarzyk, P., Pietrobelli, A., Redden, D.T., Ruden, D.M., Wang, C., Waterland, R.A., Wright, S.M., Allison, D.B. 2009. Ten putative contributors to the obesity epidemic. Critical Reviews in Food Science and Nutrition. 49(10):868-913.

Ko, Y., Liang, X., Smith, W.C., Degen, J.L., Hook, M. 2011. Binding of Efb from Staphylococcus aureus to fibrinogen blocks neutrophil adherence. Journal of Biological Chemistry. 286(11):9865-9874.

Lam, F.W., Burns, A.R., Smith, W.C., Rumbaut, R.E. 2011. Platelets enhance neutrophil transendothelial migration via P-selectin glycoprotein ligand-1. American Journal of Physiology - Heart and Circulatory Physiology. 300: H468-H475.

Li, Z., Burns, A.R., Han, L., Rumbaut, R.E., Smith, W.C. 2011. IL-17 and VEGF are necessary for efficient corneal nerve regeneration. American Journal of Pathology. 178(3):1106-16.

Gagen, D., Laubinger, S., Li, Z., Petrescu, M., Brown, E.S., Smith, W.C., Burns, A.R. 2010. ICAM-1 mediates surface contact between neutrophils and keratocytes following corneal epithelial abrasion in the mouse. Experimental Eye Research. 91: 676-684.

Yang, C., Albin, D.M., Wang, Z., Stoll, B., Lackeyram, D., Swanson, K.C., Yin, Y., Tappenden, K.A., Mine, Y., Yada, R.Y., Burrin, D.G., Fan, M.Z. 2011. Apical Na[+]-D-glucose cotransporter 1 (SGLT1) activity and protein abundance are expressed along the jejunal crypt-villus axis in the neonatal pig. American Journal of Physiology - Gastrointestinal and Liver Physiology. 300(1):G60-G70.

Gay, A.N., Lazar, D.A., Stoll, B., Naik-Mathuria, B., Mushin, O.P., Rodriguez, M.A., Burrin, D.G., Olutoye, O.O. 2011. Near-infrared spectroscopy measurement of abdominal tissue oxygenation is a useful indicator of intestinal blood flow and necrotizing enterocolitis in premature piglets. Journal of Pediatric Surgery. 46(6):1034-1040.

Suryawan, A., Davis, T.A. 2011. Regulation of protein synthesis by amino acids in muscle of neonates. Frontiers in Bioscience. 16:1445-1460.

Orellana, R.A., Wilson, F.A., Gazzaneo, M.C., Suryawan, A., Davis, T.A., Nguyen, H.V. 2011. Sepsis and development impede muscle protein synthesis in neonatal pigs by different ribosomal mechanisms. Pediatric Research. 69(6):473-478.

Suryawan, A., Davis, T.A. 2010. The abundance and activiation of mTORC1 regulators in skeletal muscle of neonatal pigs are modulated by insulin, amino acids, and age. Journal of Applied Physiology. 109(5):1448-1454.

Puiman, P.J., Jensen, M., Stoll, B., Renes, I.B., De Bruijn, A.C., Dorst, K., Schierbeek, H., Schmidt, M., Boehm, G., Burrin, D.G., Sangild, P.T., Goudoever, J.B. 2011. Intestinal threonine utilization for protein and mucin synthesis is decreased in formula-fed preterm pigs. Journal of Nutrition. 141(7):1306-1311.

Kellermayer, R., Dowd, S.E., Harris, A.R., Balasa, A., Schaible, T.D., Wolcott, R.D., Tatevian, N., Szigeti, R., Li, Z., Versalovic, J., Smith, W.C. 2011. Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice. Federation of American Societies for Experimental Biology Conference. 25: 1449-1460.

Zhijie, L., Burns, A.R., Byeseda, S.M., Smith, W.C. 2011. CCL20, (gamma)(delta) T cells, and IL-22 in corneal epithelial healing. Federation of American Societies for Experimental Biology Conference. 25: 1-10.

Tong, Q. 2011. Sirtuins as potential drug targets for metabolic diseases. In: Wang, M. editor. Metabolic Syndrome: Underlying Mechanisms and Drug Therapies. Hoboken, NJ: John Wiley & Sons, Inc. p. 391-422.

Cheng, N., Zhang, W., Chen, W.Q., Jin, J., Cui, X., Butte, N.F., Chan, L., Hirschi, K.D. 2011. A mammalian monothiol glutaredoxin, Grx3, is critical for cell cycle progression during embryogenesis. FEBS Journal. 278(14):2525-2539.

Burrin, D.G. 2011. Trophic Factors and Regulation of Gastrointestinal Tract and Liver Development. In: Polin, R.A., Fox, W.W., Abman, S.H., editors. "Fetal and Neonatal Physiology". 4th edition. Philadelphia, PA: Saunders Publishers. p. 1-7.

Wang, Y., Guan, X. 2010. GLP-2 potentiates L-type CA2+ channel activity associated with stimulated glucose uptake in hippocampal neurons. American Journal of Physiology - Endocrinology and Metabolism. 298:E156-E166.

Wang, Y., Li, X., Guo, Y., Chan, L., Guan, X. 2010. Alpha-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling in the skeletal muscle of aged mice. Metabolism: Clinical and Experimental. 59(7):967-976.

Bauchart-Thevret, C., Cui, L., Wu, G., Burrin, D.G. 2010. Arginine-induced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide. American Journal of Physiology - Endocrinology and Metabolism. 299(6):E899-E909.

Stoll, B., Horst, D.A., Cui, L., Chang, X., Ellis, K.J., Hadsell, D.L., Suryawan, A., Kurundkar, A., Maheshwari, A., Davis, T.A., Burrin, D.G. 2010. Chronic parenteral nutrition induces hepatic inflammation, steatosis and insulin resistance in neonatal pigs. Journal of Nutrition. 140(12):2193-2200.

Puiman, P.J., Stoll, B., Van Goudoever, J.B., Burrin, D.G. 2011. Enteral arginine does not increase superior mesenteric arterial blood flow and but induces mucosal growth in neonatal pigs. Journal of Nutrition. 141(1):63-70.

Taylor-Edwards, C.C., Burrin, D.G., Holst, J.J., Mcleod, K.R., Harmon, D.L. 2011. Glucagon-like peptide-2 (GLP-2) increases small intestinal blood flow and mucosal growth in ruminating calves. Journal of Dairy Science. 94(2):888-898.

Davis, T.A., Suryawan, A., Fiorotto, M.L., Orellana, R.A., Burrin, D.G. 2010. Developmental changes in insulin- and amino acid-induced mTOR signalling regulate muscle protein synthesis in neonatal pigs. In: Crovetto, G.M. editor. Proceedings of the 3rd European Association of Animal Protection International Symposium on Energy and Protein Metabolism and Nutrition, Session 4: Systemic and local regulation mechanisms, an EAAP Publication, Wageningen Academic Publishers, The Netherlands, September 6-10, 2010, Parma, Italy, 127:249-250.

Davis, T.A., Suryawan, A., Wilson, F.A., Fiorotto, M.L., Gazzaneo, M.C., Orellana, R.A., Burrin, D.G. 2010. Prolonged stimulation of protein synthesis by leucine is dependent on amino acid availability. In: Crovetto, G.M. editor. Proceedings of the 3rd European Association of Animal Protection International Symposium on Energy and Protein Metabolism and Nutrition, Session 4: Systemic and local regulation mechanisms, an EAAP Publication, Wageningen Academic Publishers, The Netherlands, September 6-10, 2010, Parma, Italy, 127:253-254.

Szentirmai, E., Kapas, L., Sun, Y., Smith, R.G., Krueger, J.M. 2010. Restricted feeding-induced sleep, activity, and body temperature changes in normal and preproghrelin-deficient mice. American Journal of Physiology. 298:R467-R477.

Palacios, O.M., Carmona, J.J., Michan, S., Chen, K.Y., Manabe, Y., Ward III, J., Goodyear, L.J., Tong, Q. 2009. Diet and exercise signals regulate SIRT3 and activate AMPK and PGC-l alpha in skeletal muscle. Aging. 1(9):771-783.

Shi, X., Li, X., Wang, Y., Zhang, K., Zhou, F., Chan, L., Li, D., Guan, X. 2011. Glucagon-like peptide-2-stimulated protein synthesis through the PI 3-kinase-dependent Akt-mTOR signaling pathway. American Journal of Physiology - Endocrinology and Metabolism. 300(3):E554-E563.

Wang, Q., Perrard, J.L., Perrard, X.D., Mansoori, A., Smith, W.C., Ballantyne, C.M., Wu, H. 2010. Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity. Obesity. 19: 505-513.

Xu, Y., Berglund, E.D., Sohn, J., Holland, W.L., Chuang, J., Fukuda, M., Rossi, J., Williams, K.W., Jones, J.E., Zigman, J.M., Lowell, B.B., Scherer, P.E., Elmquist, J.K. 2010. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nature Neuroscience. 13(12):1457-1459.

Zeev, H., Feil, R., Constancia, M., Frage, M., Junien, C., Carel, J., Boileau, P., Le Bouc, Y., Deal, C., Lillycrop, K., Scharfmann, R., Sheppard, A., Skinner, M., Szyf, M., Waterland, R.A., Waxman, D.J., Whitelaw, E., Ong, K., Albertsson-Wikland, K. 2011. Child health developmental plasticity, and epigenetic programming. Endocrine Reviews. 32(2):159-224.

Gao, X., Yong-Hyun, S., Li, M., Wang, F., Tong, Q., Zhang, P. 2010. The fat mass and obesity associated gene FTO functions in the brain to regulate postnatal growth in mice. PLoS One. 5(11):e14005.

Yang, Y., Hubbard, B.P., Sinclair, D.A., Tong, Q. 2010. Characterization of murine SIRT3 transcript variants and corresponding protein products. Journal of Cellular Biochemistry. 111:1051-1058.

Last Modified: 10/20/2017
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