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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

2010 Annual Report


4. Accomplishments
1. Disruption of circadian rhythm promotes obesity and tumor development. Human studies have indicated that a disruption of the circadian rhythm (our internal 24-hour time clock) increases the risk of obesity and cancer development in individuals that perform shift work during the night. However, the biological mechanisms leading to such risk remains unclear. Researchers at the Children's Nutrition Research Center, Houston, Texas, have recently demonstrated in mice that a disruption of the circadian rhythm induces similar types of tumor development to night-shift human workers. In addition, mice treated with chronic jet-lag also show increased risk of fatty liver development and higher body mass index without changing food choice or amount food-intake, and that uncontrolled activity of the sympathetic nervous system, which aids in the control of most of the body's internal organs, is involved in the increased tumor and obesity development under jet-lag conditions. These findings strongly suggest that educating the public to adopt a healthy life-style is important for both obesity and cancer prevention.

2. The importance of a white blood cell protein. During the development of obesity in children and adults, certain types of white blood cells migrate into fat tissue and cause some of the disease symptoms, such as diabetes, common in obese individuals. Scientists at the Children's Nutrition Research Center, Houston, Texas, are studying a protein called CD11c found on the surface of white blood cells in obese fat tissues. To determine the importance of this protein in obesity-related disease, they studied mice that were genetically engineered to be unable to make this protein. Animals that lacked CD11c became obese when put on a high fat diet, but they showed very little signs of diabetes in contrast to normal mice that developed signs of diabetes within a few weeks of eating a high fat diet. These results show for the first time that the white blood cell protein CD11c contributes to obesity-related disease, and they raise the possibility that a drug blocking CD11c could be used to reduce obesityrelated disease.

3. Studies on fat as a danger signal. Most of the body's cells have proteins on their surface that allow them to activate inflammation when they recognize different danger signals such as foreign biochemicals. Scientists at the Children's Nutrition Research Center, Houston, Texas, are studying one such protein, called TLR2, because this protein may recognize certain types of fat as a danger signal. Mice genetically engineered to be deficient in this protein when placed on a high fat diet developed very little signs of the inflammation that causes obesity-related symptoms, in contrast to normal mice that readily developed obesity and symptoms of disease. These findings show for the first time that TLR2 is involved in high fat diet-induced inflammation, and they indicate that future in-depth study of TLR2 will provide new insights into how the body responds to excess fat as a danger signal.

4. Protein production in the mitochondria. Additional knowledge is needed to better understand the regulation of cellular metabolism. Mitochondria are the structures within cells that produce power for the cells to function. SIRT3 proteins reside in mitochondria and regulate several processes in mitochondria. In collaboration with researchers at Penn State University, scientists at the Children's Nutrition Research Center found MRPL10 proteins (mitochondrial ribosomal protein L10, a part of mitochondrial machinery for the protein production) contain a type of chemical modification, namely acetylation. SIRT3 can remove this chemical modification on MRPL10 and regulate the function of MRPL10 to reduce the production of mitochondrial proteins. This is the first time such kind of control of mitochondrial protein production has been discovered.

5. Structure of an oxidative balance-regulating protein. Free radicals that often cause oxidative stress are harmful to cells and organisms and are involved in the development of some diseases; however, how cells utilize redox (oxidation and reduction balance)-sensitive proteins (enzymes) to remove the free radicals and avoid cellular damage is still largely unknown. Determination of the active elements within a protein molecule is critical toward understanding of the physiological functions of those proteins. In collaboration with The Samuel Roberts Noble Foundation, Children's Nutrition Research Center researchers produced a crystal form of one of the redoxsensitive proteins, called PICOT, and determined some important amino acid residues in this structure that may contribute to different biochemical functions related to oxidative stress. These findings will help other scientists to potentially engineer this protein to enhance cell's capacity of tolerance to oxidative damage.

6. The role of GLP-2 receptor in obesity. Diabetics cannot maintain blood glucose within normal levels, and until now the role of GLP-2 (a nutrient-responsive gut hormone) has not been explored for the potential control of blood glucose. Researchers at the Children's Nutrition Research Center, Houston, Texas, were able to quantify the synthesis of glucose (i.e., gluconeogenesis) in the liver. They have found that the GLP-2 receptor deficiency impairs liver gluconeogenesis, thus resulting in a high level of blood glucose even with high dose of insulin. This research will provide a powerful, genetically-modified mouse model to define the physiological role and signaling network of GLP-2 in the control of glucose level and energy balance, and to advance our understanding at cellular and molecular levels how glucose metabolism is disrupted in diabetes.

7. Improving preterm infant nutrition by getting a grasp on NEC. Necrotizing enterocolitis (NEC) is a serious intestinal disease in premature infants, and there is an urgent need to develop nutritional approaches to prevent NEC. Researchers at the Children's Nutrition Research Center, Houston, Texas, have completed studies testing if the type of dietary carbohydrate, either polycose (an easily digestible source of carbohydrate calories) or lactose-based formula, used in infant formulas induces NEC. Our results showed that the incidence and severity of NEC was higher in preterm animal models fed a formula containing polycose and such findings highlight the potential risk associated with poor digestion of polycose in infant formula. These results have the potential impact of modifying the design of human infant formulas since considerable evidence shows that human milk is protective against NEC and contains mainly lactose, whereas many formulas fed to preterm infants contain substantial amounts of polycose along with lactose.

8. Development of a mouse model to understand how maternal obesity during fetal development promotes obesity in the next generation. Previous studies have shown that maternal obesity promotes obesity in the next generation; but exactly when maternal obesity affects development, however, is not known. Researchers at the Children's Nutrition Research Center in Houston, Texas, have shown using a mouse model that maternal obesity during fetal development promotes excess fat levels in her offspring, whereas maternal obesity during the lactation period actually leads to lower body weight in the offspring. This is an important accomplishment in that it provides a 'cleaner' model in which we can study the effects of maternal obesity on epigenetics (developmental establishment of gene regulatory mechanisms) in the hypothalamus, and focuses the relevant period of development.

9. Gene expression profiling in mouse model liver. Nutritional protein deprivation early in life has an impact on the liver, but the long-term consequences are not known, especially if this may predispose individuals to metabolic disease. Researchers at the Children's Nutrition Research Center in Houston, Texas, have found several up- and down-regulated genes that play a role in DNA organizational structure. This will help researchers understand the mechanisms of long-term altered gene regulation after early exposure to protein deprivation.


Review Publications
Kellermayer, R., Balasa, A., Zhang, W., Lee, S., Mirza, S., Chakravarty, A., Szigeti, R., Laritsky, E., Tatevian, N., Smith, W.C., Shen, L., Waterland, R.A. 2010. Epigenetic maturation in colonic mucosa continues beyond infancy in mice. Human Molecular Genetics. 19(11):2168-2176.

Wu, H., Perrard, X.D., Wang, Q., Perrard, J.L., Polsani, V.R., Jones, P.H., Smith, W.C., Ballantyne, C.M. 2009. CD11c expression in adipose tissue and blood and its role in diet-induced obesity. Arteriosclerosis Thrombosis and Vascular Biology. 30(2):186-192.

Wilson, F.A., Suryawan, A., Gazzaneo, M.C., Orellana, R.A., Nguyen, H.V., Davis, T.A. 2010. Stimulation of muscle protein synthesis by prolonged parenteral infusion of leucine is dependent on amino acid availability in neonatal pigs. Journal of Nutrition. 140(2):264-270.

Byeseda, S.E., Burns, A.R., Dieffenbaugher, S., Rumbaut, R.E., Smith, W.C., Li, Z. 2009. ICAM-1 is necessary for epithelial recruitment of gammadelta T cells and efficient corneal wound healing. American Journal of Pathology. 175(2):571-579.

Wilson, F.A., Suryawan, A., Orellana, R.A., Kimball, S.R., Gazzaneo, M.C., Nguyen, H.V., Fiorotto, M.L., Davis, T.A. 2009. Feeding rapidly stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing translation initiation. Journal of Nutrition. 139(10):1873-1880.

Bellizzi, D., Covello, G., Di Cianni, F., Tong, Q., De Benedictis, G. 2009. Identification of GATA2 and AP-1 activator elements within the enhancer VNTR occurring in intron 5 of the human SIRT3 gene. Molecules and Cells. 28:87-92.

Lee, S., Prince, J.E., Rais, M., Kheradmand, F., Ballantyne, C.M., Weitz-Schmidt, G., Smith, C.W., Corry, D.B. 2008. Developmental control of integrin expression regulates Th2 effector homing. Journal of Immunology. 180(7):4656-4667.

Wu, H.R., Gower, R.M., Wang, H., Perrard, X.D., Ma, R., Bullard, D.C., Burns, A.R., Paul, A., Smith, C.W., Simon, S.I., Ballantyne, C.M. 2009. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation. 119(20):2708-2717.

Cheng, N. 2008. AtGRX4, an Arabidopsis chloroplastic monothiol glutaredoxin, is able to suppress yeast GRx5 mutant phenotypes and respond to oxidative stress. Federation of European Biochemical Societies Letters 582(6):848-854.

Zhao, J., Cheng, N., Motes, C.M., Blancaflor, E.B., Moore, M., Gonzales, N., Padmanaban, S., Sze, H., Ward, J.M., Hirschi, K.D. 2008. AtCHX13 is a plasma membrane K+ transporter. Plant Physiology. 148(2):796-807.

Mei, H., Cheng, N-H., Zhao, J., Park, S., Escareno, R.A., Pittman, J.K., Hirschi, K.D. 2009. Root development under metal stress in Arabidopsis thaliana requires the H(+)/cation antiporter CAX4. New Phytologist. 183(1):95-105.

Himes, R.W., Smith, W.C. 2009. Tlr2 is critical for diet-induced metabolic syndrome in a murine model. Journal of Federation of American Societies for Experimental Biology. 24(3):731-739.

Eniolola-Adefeso, O., Huang, R.B., Smith, W.C. 2009. Kinetics of LFA-1 mediated adhesion of human neutrophils to ICAM-1-role of E-selectin signaling post-activation. Annals of Biomedical Engineers. 37(4):737-748.

Wang, F., Tong, Q. 2009. SIRT2 suppresses adipocyte differentiation by deacetylating FOX01 and enhancing FOXO1's repressive interaction with PPAR gamma. Molecular Biology of the Cell. 20:801-808.

Burrin, D.G., Stoll, B. 2009. Metabolic fate and function of dietary glutamate in the gut. American Journal of Clinical Nutrition. 90(suppl):1S-7S.

Puiman, P., Stoll, B. 2008. Animal models to study neonatal nutrition in humans. Current Opinion in Clinical Nutrition and Metabolic Care. 11:601-606.

Naik-Mathuria, B., Pilling, D., Crawford, J.R., Gay, A.N., Smith, C.W., Gomer, R.H., Olutoye, O.0. 2008. Serum amyloid P inhibits dermal wound healing. Journal of Wound Repair and Regeneration. 16(2):266-273.

Naik-Mathuria, B., Gay, A.N., Yu, L., Hsu, J.E., Smith, C., Olutoye, O.0. 2008. Fetal wound healing using a genetically modified murine model: The contribution of P-selectin. Journal of Pediatric Surgery. 43(4):675-82.

Wu, G., Bazer, F.W., Davis, T.A., Kim S.W., Li, P., Rhoads, J.M., Satterfield, M.C., Smith, S.B., Spencer, T.E., Yin, Y. 2009. Arginine metabolism and nutrition in growth, health and disease. Amino Acids. 37(1):153-168.

Orellana, R.A., Suryawan, A., Kimball, S.R., Wu, G., Nguyen, H.V., Jefferson, L.S., Davis, T.A. 2008. Insulin signaling in skeletal muscle and liver of neonatal pigs during endotoxemia. Pediatric Research. 64(5):505-510.

Suryawan, A., O'Connor, P.M.J., Bush, J.A., Nguyen, H.V., Davis, T.A. 2009. Differential regulation of protein synthesis by amino acids and insulin in peripheral and visceral tissues of neonatal pigs. Amino Acids. 37(1):97-104.

Waterland, R.A. 2008. Epigenetic epidemiology of obesity: Application of epigenomic technology. Nutrition Reviews. 66(Suppl. 1):S21-S23.

Waterland, R.A. 2009. Is epigenetics an important link between early life events and adult disease? Hormone Research. 71(Suppl. 1):13-16.

Bauchart-Thevret, C., Stoll, B., Chako, S., Burrin, D.G. 2009. Sulfur amino acid deficiency upregulates intestinal methionine cycle activity and suppresses epithelial growth in neonatal pigs. American Journal of Physiology - Endocrinology and Metabolism. 296:E1239-E1250.

Young, M.E. 2008. Case 22:Type II diabetes. In: Toy, E.C., Seifert, W.E., Strobel, H.W., Harms, K.P., editors. Case Files: Biochemistry. 2nd Edition. New York, NY: McGraw-Hill Medical. p.198-207.

Skokowa, J., Lan, D., Thakur, B.K., Wang, F., Gupta, K., Cario, G., Brechlin, A.M., Schamback, A., Hinrichsen, L., Meyer, G., Gaestel, M., Stanulla, M., Tong, Q., Welte, K. 2009. NAMPT is essential for the G-CSF-induced myeloid differentiation via a NAD+-sirtuin-1-dependent pathway. Nature Medicine. 15(2):151-158.

Bauchart-Thevret, C., Stoll, B., Burrin, D.G. 2009. Intestinal metabolism of sulfur amino acids. Nutrition Research Reviews. 22:175-187.

Thymann, T., Moller, H.K., Stoll, B., Stoy, A.C., Buddington, R.K., Bering, S., Jensen, B.B., Olutoye, O.O., Siggers, R.H., Molbak, L., Sangild, P.T., Burrin, D.G. 2010. Carbohydrate maldigestion induces necrotizing enterocolitis in preterm pigs. American Journal of Physiology. 297:G1115-G1125.

Verbruggen, S., Sy, J., Gordon, W.E., Hsu, J., Wu, M., Chacko, S., Zurakowski, D., Burrin, D., Castillo, L. 2009. Ontogeny of methionine utilization and splanchnic uptake in critically ill children. American Journal of Physiology - Endocrinology and Metabolism. 297(5):E1046-E1055.

Li, L., Cheng, NH., Hirschi, K.D., Wang, X. 2010. Structure of "Arabidopsis" chloroplastic monothiol glutaredoxin AtGRXcp. Acta Crystallographica, Section D: Biological Crystallography. D66(Part 6):725-732.

Benight, N.M., Burrin, D.G., Stoll, B. 2009. Intestinal metabolism of sulfur amino acids. In: Masella, R., Mazza, G., editors. Glutathione and Sulfur Amino Acids in Human Health and Disease. New Jersey, NJ: Wiley & Sons, Inc. p. 47-72.

Last Modified: 05/26/2017
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