Page Banner

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

2013 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:
Significant research progress was accomplished during the year. To review the progress, please refer to project 6250-51000-055-10S (Project 1), 6250-51000-055-20S (Project 2), 6250-51000-055-30S (Project 3), 6250-51000-055-40S (Project 4), and 6250-51000-055-50S (Project 5)


4. Accomplishments


Review Publications
Burrin, D.G., Davis, T.A. 2013. Mechanism of nutrient sensing. In: Ross, A.C., Caballero, B., Cousins, R.J., Tucker, K.L., Ziegler, T.R., editors. Modern Nutrition in Health and Disease, 11th edition, Part II. Nutritional roles in integrated biologic systems, Section B. Digestive, endocrine, immune, and neural mechanisms, Chapter 47. Philadelphia, PA:Wolters Kluwar-Lippincott, Williams & Wilkins Publishers. p. 626-632.

Moore, D.D. 2012. Nuclear receptors reverse McGarry's vicious cycle to insulin resistance. Cell Metabolism. 15:615-622.

Wang, J., Perrard, X.D., Mukherjee, A., Rosales, C., Chen, Y., Smith, C.W., Pownall, H.J., Ballantyne, C.M., Wu, H. 2012. ApoE and the role of very low density lipoproteins in adipose tissue inflammation. Atherosclerosis. 223(2):342-349.

Schaible, T.D., Harris, R.A., Dowd, S.E., Smith, C.W., Kellermayer, R. 2011. Maternal methyl-donor supplementation induces prolonged murine offspring colitis susceptibility in association with mucosal epigenetic and microbiomic changes. Human Molecular Genetics. 20(9):1687-1696.

Wu, Q., Lin, J., Liu, J., Wang, X., Lim, W., Oh, M., Park, J., Rakasjelar, C., Whitham, S.A., Cheng, N., Hirschi, K.D., Park, S. 2012. Ectopic expression of Arabidopsis glutaredoxin AtGRXS17 enhances thermotolerance in tomato. Plant Biotechnology Journal. 945-955.

Wang, Q., Perrard, X.D., Perrard, J.L., Mansoori, A., Raya, J.L., Hoogeveen, R., Smith, C.W., Ballantyne, C.M., Wu, H. 2011. Differential effect of weight loss with low-fat diet or high-fat diet restriction on inflammation in the liver and adipose tissue of mice with diet-induced obesity. Atherosclerosis. 219(1):100-108.

Stoll, B., Puiman, P.J., Cui, L., Chang, X., Benight, N.M., Bauchart-Thevret, C., Hartman, B., Holst, J.J., Burrin, D.G. 2012. Continuous parenteral and enteral nutrition induces metabolic dysfunction in neonatal pigs. Journal of Parenteral and Enteral Nutrition. 36(5):538-550.

Bauchart-Thevret, C., Cottrell, J., Stoll, B., Burrin, D.G. 2011. First-pass splanchnic metabolism of dietary cysteine in weanling pigs. Journal of Animal Science. 89(12):4093-4099.

Benight, N.M., Stoll, B., Marini, J.C., Burrin, D.G. 2012. Preventative oral methylthioadenosine is anti-inflammatory and reduces DSS-induced colitis in mice. American Journal of Physiology - Gastrointestinal and Liver Physiology. 303(1):G71-G82.

Bauchart-Thevret, C., Stoll, B., Benight, N.M., Olutoye, O., Lazar, D., Burrin, D.G. 2013. Supplementing monosodium glutamate to partial enteral nutrition slows gastric emptying in preterm pigs. Journal of Nutrition. 143(5):563-570.

Benight, N.M., Stoll, B., Olutoye, O.O., Holst, J.J., Burrin, D.G. 2013. GLP-2 delays but does not prevent the onset of necrotizing enterocolitis in preterm pigs. Journal of Pediatric Gastroenterology and Nutrition. 56(6):623-630.

Puiman, P., Stoll, B., Molbak, L., De Bruijn, A., Schierbeek, H., Boye, M., Boehm, G., Renes, I., Van Goudoever, J., Burrin, D.G. 2013. Modulation of the gut microbiota with antibiotic treatment suppresses whole body urea production in neonatal pigs. American Journal of Physiology - Gastrointestinal and Liver Physiology. 304(3):G300-G310.

Taylor-Edwards, C.C., Burrin, D.G., Kristensen, N.B., Holst, J.J., McLeod, K.R., Harmon, D.L. 2012. Glucagon-like peptide-2 (GLP-2) increases net amino acid utilization by the portal-drained viscera of ruminatinhg calves. Animal. 6(12):1985-1997.

Waterland, R.A. 2012. Nutritional epigenetics. In: Erdman, J.W., MacDonald, I.A., Zeisel, S.H., editors. Present Knowledge in Nutrition. 10th Edition. Oxford, UK: Wiley-Blackwell. p. 14-26.

Lin, L., Pang, W., Chen, K., Wang, F., Gengler, J., Sun, Y., Tong, Q. 2012. Adipocyte expression of PU.1 transcription factor causes insulin resistance through upregulation of inflammatory cytokine gene expression and ROS production. American Journal of Physiology - Endocrinology and Metabolism. 302:E1550-E1559.

Van Der Velde, M., Ven Der Eerden, B., Sun, Y., Almering, J., Van Der Lely, A., Delhanty, P., Smith, R.G., Van Leeuwen, J. 2012. An age-dependent interaction with leptin unmasks ghrelin's bone-protective effects. Endocrinology. 153(8):3593-3602.

Wang, Y., Xuemei, S., Qi, J., Li, X., Uray, K., Guan, X. 2012. SIRT1 inhibits the mouse intestinal motility and epithelial proliferation. American Journal of Physiology - Gastrointestinal and Liver Physiology. 302:G207-G217.

Kim, K., Sohn, J., Kohno, D., Xu, Y., Williams, K., Elmquist, J.K. 2011. SF-1 in the ventral medial hypothalamic nucleus: A key regulator of homeostasis. Molecular and Cellular Endocrinology. 336(1-2):219-223.

Gazzaneo, M.C., Orellana, R.A., Suryawan, A., Tuckow, A.P., Kimball, S.R., Wilson, F.A., Nguyen, H.V., Torrazza, R.M., Fiorotto, M.L., Davis, T.A. 2011. Differential regulation of protein synthesis and mTOR signaling in skeletal muscle and visceral tissues of neonatal pigs after a meal. Pediatric Research. 70(3):253-260.

Kim, K., Zhao, L., Donato Jr., J., Kohno, D., Xu, Y., Elias, C.F., Lee, C., Parker, K.L., Elmquist, J.K. 2011. Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus. Proceedings of the National Academy of Sciences. 108(26):10673-10678.

Xu, Y., Elmquist, J.K., Fukuda, M. 2011. Central nervous control of energy and glucose balance: Focus on the central melanocortin system. Annals of the New York Academy of Sciences. 1243(1):1-14.

Xu, Y., Nedungadi, T.P., Zhu, L., Sobhani, N., Irani, B.G., Davis, K.E., Zhang, X., Zou, F., Gent, L.M., Hahner, L.D., Khan, S.A., Elias, C.F., Elmquist, J.K., Clegg, D.J. 2011. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metabolism. 14(4):453-465.

Sohn, J., Xu, Y., Jones, J.E., Wickman, K., Williams, K.W., Elmquist, J.K. 2011. Serotonin 2C receptor activates a distinct population of arcuate pro-opiomelanocortin neurons via TRPC channels. Neuron. 71(3):488-497.

Nagy-Szakal, D., Hollister, E.B., Luna, R., Szigetti, R., Tatevian, N., Smith, C.W., Versalovic, J., Kellermayer, R. 2013. Cellulose supplementation early in life ameliorates colitis in adult mice. PLoS One. 8(2):e56685.

Burrin, D.G., Stoll, B., Moore, D. 2013. Intestinal bile acid sensing is linked to key endocrine and metabolic signalng pathways. Journal of Animal Science. 91(5):1991-2000.

Chen, M., Tong, Q. 2013. An update on the regulation of adipogenesis. Drug Discovery Today: Disease Mechanisms. 10(1-2):e15-e19.

Gao, Y., Li, Z., Hassan, N., Mehta, P., Burns, A.R., Tang, X., Smith, C.W. 2013. NK cells are necessary for recovery of corneal CD11c+ dendritic cells after epithelial abrasion injury. Journal of Leukocyte Biology. 94:(2)343-351.

Last Modified: 10/20/2017
Footer Content Back to Top of Page