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United States Department of Agriculture

Agricultural Research Service

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Location: Arkansas Children's Nutrition Center

2010 Annual Report

1a. Objectives (from AD-416)
Dietary factors may significantly impact long-term human health during adult life as a result of the influences on early developmental events. Certain common dietary factors appear to be capable of affecting growth and development; transiently and permanently altering metabolism; influencing body composition; and 4) preventing some diseases. For example, fruits, vegetables, grains, and milk contain natural compounds (phytochemicals, peptides, and proteins) that can alter development, physiology, and metabolism, which can ultimately lead to disease prevention and phenotypic changes. Additionally isoflavones are particularly concentrated in soybeans and can have many of the same actions as the major female hormones in women, the estrogens. Countries with regular consumption of large amounts of soy foods report lower incidence of cancer, cardiovascular disease, and obesity; and factors in soy (isoflavones and peptides) are postulated as being partially responsible. The objectives of our research include: 1) determine the effects of diet and physical activity in humans and animal models on development and organ function; 2) determine how early exposure to soy proteins and fruits confers resistance to chronic diseases such as mammary cancer, cardiovascular disease, and type 2 diabetes in later adult life; 3) evaluate multiple molecular mechanisms and identify bioactive components for chronic disease prevention by diets using appropriate models as measured by tumor suppressors and oncogenes; oxidative modification; inflammation; immunomodulation; and insulin sensitivity; 4) examine consequences of early intake of combinations of foods (soy, fruits) on chronic disease prevention, organ development and signaling pathways, relative to dietary intake of a single food; 5) investigate the mechanisms of maternal obesity-induced fetal programming; 6) examine the impact of type and amount of dietary macronutrient components on development of obesity and associated metabolic sequence in an animal model of pediatric total enteral nutrition and in clinical studies; 7) identify the potential of dietary factors for mitigating risk of obesity via nutritional programming; and 8) determine the effects of genetic and epigenetic interactions with diet, nutritional status, weight gain, and behavior during gestation on placental and offspring development, health and susceptibility to chronic diseases, including obesity. It is essential to ascertain the long-term health consequences, both positive and negative, of early consumption of these phytochemicals since it may impact a major segment of our American population.

1b. Approach (from AD-416)
Studies will focus on the various dietary factors found in foods commonly consumed by children, such as infant formula, fruits, rice, milk, and soy, to determine their long-term health effects in infants and children. We will analyze how the early exposure to protein sources and fruits normally consumed by infants and children prevents the initiation of and protects against chronic diseases by altering tissue differentiation, inflammation, and/or oxidative status. We will use animal models to mechanistically address the molecular and cellular pathways regulated by intake of various dietary factors (such as in; soy foods, berries, grains and milk) in mammary tissue, aorta, liver, adipose tissue, pancreas, and skeletal muscle; identify tissue and serum biomarkers of healthy status associated with these diets; and provide new molecular targets and processes underlying chronic diseases that may be influenced by proper nutrition. Additional work will be undertaken in an observational study of infants from birth to age 6 years, The Beginnings Study. Breast-fed, milk formula-fed, and soy formula-fed children are studied for growth, development, body composition, and metabolism. In addition, bone development, and immune system development and function will be studied in children, and animal models will be utilized to explore molecular mechanisms underlying the effects of early dietary exposures. The rat model will be used to understand the parental genetic transmission of the susceptibility to high fat feeding to future generations and underlying molecular, biochemical, and endocrine mechanisms, in the offspring. Work will be accomplished by evaluating critical periods of development and vulnerable stages of life (i.e. the nutritional status of women at the moment of conception; nutritional and developmental issues during pregnancy and lactation) and the development of eating behaviors during childhood, adolescence, and later stages of life.

3. Progress Report
During FY2010, ACNC researchers studied the biological consequences and underlying mechanisms associated with dietary exposure to foods purported to prevent chronic diseases, including breast cancer, metabolic syndrome, and heart disease. Using mice and rats models of these diseases, we found that consumption of soy proteins, rice, and fruits elicited multiple, non-overlapping biological responses in target tissues. To address whether soy protein acts like an estrogen, we studied genes in the breast of female rats that were either fed soy or that were treated with estrogen (E2). We determined that soy-fed rats did not turn-on or turn-off the same genes as E2-treated rats, and concluded that soy does not act like an estrogen. These are significant findings relative to safety of soy formula. We also conducted a systematic evaluation of effects of consuming berries (blueberry, black raspberry, cranberry) on the development of metabolic syndrome. All berries reduced plasma triglyceride levels in mice fed a high fructose diet, suggesting a potential therapeutic application in preventing metabolic syndrome. Blueberry-fed rats have remarkable increases in bone density, and compounds in blueberry (phenolic acids) appear to be responsible. Offspring born to obese rat mothers become severely obese relative to offspring of lean mothers even though the same calories were eaten. Thus, obese mothers can "program" their offspring to metabolize differently and store more energy as fat. The offspring had: 1) increased ability to convert food energy into fat; 2) decreased ability to break down fat; and 3) changes in hormones that regulate metabolism. These studies have profound implications and suggest that maternal obesity during pregnancy may be a major cause of the current obesity epidemic. In an ongoing and longitudinal protocol, we are continuing to study growth and brain development of children (birth to age 6 y) fed breast milk, milk formula or soy formula during their first year. We started clinical studies to translate animal findings on obesity to human subjects and to determine how overweight pregnant women may promote childhood obesity. Enrollment into a prospective longitudinal study of weight gain and body composition in infants born to lean or overweight women was started. Thus, this is translational research into maternal programming of fetal metabolism leading to childhood obesity. Because the placenta is an important link between a mother and her fetus during pregnancy, we are collecting placentas to establish a "placental tissue bank" to be shared with scientists worldwide.

4. Accomplishments
1. A new state-of-the-art instrument to measure children's body composition is validated. Until now, there has been no single technology or instrument that allows investigators to determine the body composition (fat, muscle, bone, and water) of children from birth through puberty. The Arkansas Children's Nutrition Center in Little Rock, Arkansas, commissioned a unique Nuclear Magnetic Resonance (NMR) machine to be built to accommodate study of children from birth (approximately 6 pounds) through 120 pounds. ACNC scientists successfully validated the usefulness of the NMR instrument in animal models of the similiar size as the children they plan to study in future protocols. This technology and instrument will allow researchers to study the children in the same instrument in longitudinal studies from birth and greatly improve the precision and accuracy of our research measurements.

2. Overweight mothers "program" energy balance in offspring. The worldwide epidemic of obesity has developed rapidly over only a few generations, and the correlation between a mother's obesity and childhood obesity is much stronger than with the father's level of obesity. This suggests that additional factors associated with the intrauterine environment of overweight women may predispose their child to obesity. Data from scientists at the Arkansas Children's Nutrition in Little Rock, Arkansas, suggest that fetal exposure to an overweight mother during pregnancy programs several hormonal systems that regulate energy balance in babies and causes fat accumulation. These data suggest that overweight pregnant rats send signals to the fetus that permanently change the way their offspring metabolize energy. This has important implications for strategies to prevent childhood obesity in children of overweight or obese women.

3. Pediatric obesity and metabolic syndrome develop after overfeeding of high fat diets despite increases in serum adiponectin. There are few rodent models in which diet-induced obesity has been developed prior to puberty and in which the metabolic consequences of childhood obesity can be studied. Scientists at the Arkansas Children's Nutrition in Little Rock, Arkansas, have developed a new model of childhood obesity using young male rats that develop insulin resistance and fat droplets in liver and muscle similar to what is observed in obese children. This occurs despite increases in a fat derived hormone, adiponectin, which is thought to be important in development of metabolic syndrome in adults. These results suggest significant differences in the endocrine and metabolic consequences of obesity in children and adults, and may provide the basis for a new understanding of the causes and potential prevention and treatment of childhood obesity.

4. Feeding rice protein isolate protects against metabolic syndrome resulting from Western diets. Insulin resistance and elevated serum lipids (cholesterol and triglycerides), which are risk factors for type 2 diabetes, cardiovascular disease and fatty liver disease, are more commonly found in "Western" populations (US and Europe) than in Asian populations. One of the many dietary differences found between "Western" and Asian populations is the amount of rice and rice products. Arkansas Children's Nutrition scientists in Little Rock, Arkansas, have demonstrated that the consumption of rice protein isolate, a protein produced from rice germ, can reverse liver fat accumulation in animals fed "Western" diets high in saturated fat and cholesterol. These results suggest significant health benefits could be achieved with increased consumption of rice products by the American population.

5. Early blueberry consumption improves bone quality. Osteoporosis is a major age-related disease with a high cost to the health care system. One way to push osteoporosis to an older age is to have a greater peak bone mass at the age when bone usually starts to decline, such as at menopause for women. Scientists at the Arkansas Children's Nutrition in Little Rock, Arkansas, have found that blueberries were highly effective in increasing bone density. These results indicate that increasing berry consumption in children's diet may be a major means of increasing bone quality and reducing later risk of osteoporosis and suggest the potential for development of phytochemical-based medicines for treatment of bone disease.

6. Early fruit consumption and breast health. Breast cancer risk is highly modified by environmental factors including diet. Foods such as fruits, may reduce the incidence of adult onset of chronic diseases, including breast cancer. Scientists at the Arkansas Children's Nutrition Center in Little Rock, Arkansas, evaluated blueberry effects on development of the mammary gland using rat and mouse models. They found that early exposure to blueberry-supplemented diets promoted mammary gland maturation in rats and mice, as well as increased production of the "tumor suppressors proteins" (PTEN and E-cadherin). These results provide strong support for the healthy benefits of increased fruit consumption at an early stage of mammary development for breast cancer protection.

7. Berry consumption, dyslipidemia and insulin resistance with high fructose consumption. Many health professionals have linked high levels of dietary fructose found in soft drinks and processed foods to childhood obesity and metabolic disorders. Results from several studies suggest that dietary factors in berries may help normalize this condition. Scientists at the Arkansas Children's Nutrition Center in Little Rock, Arkansas, evaluated the effects of dietary blueberries, black raspberries and cranberries on the development of elevated blood triglycerides (dyslipidemia) and insulin insensitivity associated with metabolic syndrome in young male rats fed a high fructose diet. Consumption of these berries reduced fasting plasma triglyceride and insulin levels, with black raspberry being the most effective. These findings raise the possibility of the therapeutic potential of berries in treatment or prevention of metabolic disorders.

8. Do berries prevent colon cancer and obesity? Although blueberries are alleged to reduce obesity, improve insulin sensitivity and prevent cancer, strong evidence for these effects is lacking. Scientists at the Arkansas Children's Nutrition Center in Little Rock, Arkansas, have completed a series of studies to address some of these issues in rodent models. They were unable to find a robust colon cancer-preventive effect of a diet containing whole blueberries. Although whole berries were not able to normalize serum lipid profiles in mice fed an obesigenic diet, juices or phytochemicals purified from the berries did partially reduce colon cancer. Thus, consumption of the whole fruit may not be as beneficial as the processed blueberries in colon health.

9. Infant formula stimulates bone formation in newborns relative to breast feeding. Infants fed soy formula are the only segment of the American population that eats significant amounts of soy foods, and research (in animal models) has shown that diets containing soy increased the individual's bone quality. Scientists at the Arkansas Children's Nutrition in Little Rock, Arkansas, have conducted studies comparing bone development in newborn animal models to determine if soy formula would cause increased bone development relative to breast-fed or milk formula fed models. Interestingly, models fed either cow-milk formula or soy formula had better quality bone than breast-fed piglets. The scientists went on to determine the mechanisms underlying this effects and found that these formula stimulate bone formation though a pathway involving specific bone proteins. These results suggest that infant formula may increase bone quality in children, thereby increasing peak bone mass in adults, and lowering the risk of osteoporosis later in life.

10. Consumption of soy protects against development of metabolic syndrome. Many chronic health problems, such as metabolic syndrome, are found at much higher rates in Western populations than in Asian populations. In most cases, metabolic syndrome occurs secondary to development of obesity as a result of eating typical "Western" diets which are high in saturated fat and cholesterol. Traditional Asian diets, by contrast are rich in vegetable proteins, especially those from soy beans. Scientists at the Arkansas Children's Nutrition in Little Rock, Arkansas, compared the effects of feeding a high fat, high cholesterol "Western" diet versus a traditional Asian diet during early development. Reduced weight gain, plasma cholesterol and increased sensitivity to insulin were found in soy-fed rats, which suggests that increasing dietary soy consumption may help prevent development of heart disease and type II diabetes in the U.S. population. Such research is an indication of the positive health benefits of consuming soy-based diets.

Review Publications
Gilchrist, J.M., Moore, M.B., Andres, A., Estroff, J.A., Badger, T.M. 2010. Ultrasonographic patterns of reproductive organs in infants fed soy formula: Comparisons to infants fed breast milk and milk formula. Journal of Pediatrics. 156(2):215-220.

Prior, R.L., Wu, X., Gu, L., Hager, T., Hager, A., Wilkes, S., Howard, L. 2009. Purified berry anthocyanins but not whole berries normalize lipid parameters in mice fed an obesogenic high fat diet. Molecular Nutrition and Food Research. 53(11):1406-1418.

Prior, R.L. 2009. Antioxidant status in vivo: the case for regular consumption of antioxidant rich fruits and vegetables. Acta Horticulturae. (ISHS) 841:75-84.

Kang, J., Li, Z., Wu, T., Jensen, G.S., Schauss, A.G., Wu, X. 2010. Antioxidant capacities and anti-inflammatory effects of flavonoid compounds isolated from acai pulp (Euterpe oleracea Mart.). Food Chemistry. 122(3):610-617.

Simmen, R.C., Pabona, J.M., Velarde, M., Simmons, C.D., Rahal, O., Simmen, F.A. 2010. The emerging role of krüppel-like factors in endocrine-responsive cancers of female reproductive tissues. Endocrinology. 204(3):223-231.

Wahl, E.C., Aronson, J., Liu, L., Skinner, R.A., Miller, M.J., Cockrell, G.E., Fowlkes, J.L., Thrailkill, K.M., Bunn, R.C., Ronis, M.J., Lumpkin, C.K. 2010. Direct bone formation during distraction osteogenesis does not require TNF alpha receptors and elevated serum TNF alpha fails to inhibit bone formation in TNFR1 deficient mice. Bone. 46(2):410-417.

White, B.L., Howard, L.R., Prior, R.L. 2010. Polyphenolic composition and antioxidant capacity of extruded cranberry pomace. Journal of Agricultural and Food Chemistry. 58(7):4037-4042.

Prior, R.L., Wilkes, S., Rogers, T., Khanal, R., Wu, X., Howard, L. 2010. Purified blueberry anthocyanins and blueberry juice alter development of obesity in mice fed an obesogenic high fat diet. Journal of Agricultural and Food Chemistry. 58(7):3970-3976.

Khanal, R.C., Howard, L.R., Prior, R.L. 2009. Procyanidin content of grape seed and pomace, and total anthocyanin content of grape pomace as affected by extrusion processing. Journal of Food Science. 74(6):H174-H182.

White, B.L., Howard, L.R., Prior, R.L. 2009. Proximate and polyphenolic characterization of cranberry pomace. Journal of Agricultural and Food Chemistry. 58(7):4030-4036.

Wu, X., Rahal, O., Kang, J., Till, S.R., Prior, R.L., Simmen, R.C. 2009. In utero and lactational exposure to blueberry via maternal diet promotes mammary epithelial differentiation in prepubescent female rats. Nutrition Research. 29(11):802-811.

Nagarajan, S. 2010. Mechanisms of anti-atherosclerotic functions of soy-based diets. Journal of Nutritional Biochemistry. 21(4):255-260.

Simmons, C., Pabona, J., Zeng, Z., Velarde, M., Gaddy, D., Simmen, F., Simmen, R. 2010. Response of adult mouse uterus to early disruption of estrogen receptor-alpha signaling is influenced by Krüppel-like factor 9. Journal of Endocrinology. 205(2):147-157.

Pabona, J., Zeng, Z., Simmen, F.A., Simmen, R.C. 2010. Functional Differentiation of Uterine Stromal Cells Involves Cross-regulation between Bone Morphogenetic Protein 2 and Kruppel-like Factor (KLF) Family Members KLF9 and KLF13. Endocrinology. 151(7):3396-3406.

Simmen, F.A., Frank, J.A., Wu, X., Xiao, R., Hennings, L.J., Prior, R.L. 2009. Lack of efficacy of blueberry in nutritional prevention of azoxymethane-initiated cancers of rat small intenstions and colon. BioMed Central (BMC) Gastroenterology. 9(1):67-76.

Wahl, E.C., Aronson, J., Liu, L., Fowlkes, J.L., Thrailkill, K.M., Bunn, R.C., Skinner, R.A., Miller, M.J., Cockrell, G., Clark, L.M., Ou, Y., Isales, C.M., Badger, T.M., Ronis, M.J., Sims, J., Lumpkin, C.K. 2010. Restoration of regenerative osteoblastogenesis in aged mice: Modulation of TNF. Journal of Bone and Mineral Research. 25(1):114-123.

Andres, A., Mitchell, A.D., Badger, T.M. 2010. QMR: Validation of an infant and children body composition instrument using piglets against chemical analysis. International Journal of Obesity. 34(4):775-80.

Prior, R.L., Rogers, T.R., Khanal, R.C., Wilkes, S.E., Wu, X., Howard, L.R. 2010. Urinary excretion of phenolic acids in rats fed cranberry. Journal of Agricultural and Food Chemistry. 58(7):3940-3946.

Khanal, R.C., Howard, L.R., Prior, R.L. 2009. Procyaidin composition of selected fruits and fruit byproducts is affected by extraction method and variety. Journal of Agricultural and Food Chemistry. 57(19):8839-8843.

Prior, R.L., Wilkes, S., Rogers, T., Khanal, R., Hager, T., Hager, A., Wu, X., Howard, L. 2010. Dietary black raspberry anthocyanins or processed black raspberry products do not alter development of obesity in mice fed an obesogenic high fat diet. Journal of Agricultural and Food Chemistry. 58(7):3977-3983.

Chen, J., Lazarenko, O.P., Shankar, K., Blackburn, M.L., Badger, T.M., Ronis, M.J. 2010. A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of wnt/beta-catenin signaling. Journal of Bone and Mineral Research. 25(5):1117-1127.

Shankar, K., Harrell, A., Kang, P., Singhal, R., Ronis, M.J., Badger, T.M. 2010. Carbohydrate-responsive gene expression in adipose tissue of rats. Endocrinology. 151(1):153-164.

Ronis, M.J., Korourian, S., Blackburn, M., Badeaux, J., Badger, T.M. 2010. The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat. Alcohol. 44(2):157-169.

Shankar, K., Kang, P., Harrell, A., Zhong, Y., Marecki, J.C., Ronis, M.J., Badger, T.M. 2010. Maternal overweight programs insulin and adiponectin signaling in the offspring. Endocrinology. 151(6):2577-2589.

White, B., Howard, L.A., Prior, R.L. 2010. Release of bound procyanidins from cranberry pomace by alkaline hydrolysis. Journal of Agricultural and Food Chemistry. 58(13):7572-7579.

Kang, J., Badger, T.M., Ronis, M.J., Wu, X. 2010. Non-isoflavone phytochemicals in soy and their health effects. Journal of Agricultural and Food Chemistry. 58(14):8119-8133.

Wu, X., Kang, J., Xie, C., Burris, R., Ferguson, M.E., Badger, T.M., Nagarajan, S. 2010. Dietary blueberries sttenuate atherosclerosis in apolipoprotein E-deficient mice by upregulating antioxidant enzymes expression. Journal of Nutrition. 140(9):1628-2632.

Klein, M.A., Nahin, R.L., Messina, M.J., Rader, J.I., Thompson, L.U., Badger, T.M., Dwyer, J.T., Kim, Y.S., Pontzer, C.H., Starke-Reed, P.E., Weaver, C.M. 2010. Guidance from an NIH workshop on designing,implementing, and reporting clinical studies of soy interventions. Journal of Nutrition. 140(6):1192S-1204S.

Rahal, O., Simmen, R.C. 2010. PTEN and p53 cross-regulation induced by soy isoflavone genistein promotes mammary epithelial cell cycle arrest and lobuloalveolar differentiation. Carcinogenesis. 31(8):1491-1500.

Dave, B., Wynne, R., Su, Y., Korourian, S., Chang, J.C., Simmen, R.C. 2010. Enhanced mammary progesterone receptor-A isoform activity in the promotion of mammary tumor progression by dietary soy in rats. Nutrition and Cancer. 62(2):774-782.

Robbins, R.J., Leonczak, J., Johnson, J.C., Li, J., Kwik-Uribe, C., Prior, R.L., Gu, L. 2009. Method performance and multi-laboratory assessment of a normal phase HPLC/FLD method for the quantitation of flavanols and procyanidins in cocoa and chocolate containing samples. Journal of Chromatography A. 1216(24):4831-4840.

Yu, S., Li, Q., Badger, T.M., Fang, N. 2009. Quantitative analysis of polar lipids in the nanoliter level of rat serum by liquid chromatography/mass spectrometry/mass spectrometry. Experimental Biology and Medicine. 234(2):157-163.

Ronis, M., Badeaux, J.V., Chen, Y., Badger, T.M. 2010. Rice Protein isolate improves lipid and glucose homeostasis in rats fed high fat/high cholesterol diets. Experimental Biology and Medicine. 235(9):1102-1113.

Last Modified: 06/23/2017
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