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United States Department of Agriculture

Agricultural Research Service

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Location: Arkansas Children's Nutrition Center

2011 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 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
Studies occurred in pregnant women and rodents, human and animal placentas, and infants/children, and were translational, clinical, or basic in nature, aimed at learning how diet, nutritional status, and dietary factors affect normal child development and disease prevention. We began translational/clinical studies to translate the animal findings to human subjects and to determine how pregnant women permanently program the metabolism of their offspring that leads to obesity. Clinical studies conducted included: studies of the eggs (oocytes) from women of differing nutritional and body composition status (lean vs. obese); studies of pregnant women; and studies of placentas. These are longitudinal studies of early periods of life: just prior to or immediately after conception (peri-conceptional); during pregnancy; and infancy. We suspect that a large amount of childhood obesity is caused by maternal programming of offspring metabolism, and these studies test that hypothesis. In the Beginnings Study, we are comparing growth, development and body composition of breast-fed or formula-fed (milk-based or soy-based) children. Unique data is being generated on normal child development with these three infant diets. Basic studies include animal studies on the physiological and biochemical effects and gene expression patterns in liver, bone, and mammary gland associated with early feeding of soy protein isolate (SPI) (the protein component of soy infant formula), rice protein isolate (RPI) (widely used in processed foods), and blueberries. SPI and RPI were found to protect against metabolic syndrome. All diets were protective against development of cardiovascular disease which appears to be associated with antioxidant and anti-inflammatory actions. An important research area is related to "if soy is an estrogen". We found that none of the beneficial health effects of SPI act through estrogen-dependent mechanisms. Thus, soy foods are not acting like an estrogen. In fact, gene expression patterns in liver, bone, and mammary gland suggest little overlap between soy and estrogen profiles and anti-estrogenic effects when SPI feeding and estrogen treatment are combined. Blueberries appear to block inflammation and stimulate bone growth through the actions of phenolic acid metabolites of the berry pigments produced by the actions of gut bacteria. We developed a new rat model of pediatric obesity, metabolic syndrome, and nonalcoholic fatty liver disease (NAFLD) by overfeeding a high fat diet via total enteral nutrition during early development. Using rodent models of diseases, we found that soy prevents the unregulated growth of mammary epithelial cells that leads to breast cancer and defined mammary stem/progenitor cells as new targets of dietary factors for breast cancer protection. Consumption of blueberries was found to prevent mammary cancer and the mechanism may be through certain phenolic acids that appear in serum of mice fed blueberries.

4. Accomplishments
1. Childhood obesity inhibits bone formation as a result of increased fatty acids. The relationship between obesity and bone health remains unclear, particularly in children. In part this is because the potentially harmful effects of obesity on bone (poor bone health) are counteracted by the positive effects (bone formation) caused in response to increased body mass (known as load-bearing effects). Scientists at the Arkansas Children's Nutrition Center in Little Rock, AR, used a new rat model in which fat mass is increased independently of body weight in young animals by feeding high fat diets though a stomach tube to show that bone formation is blocked as a result of direct action of fatty acids (known as NEFA) released from growing fat pads on bone cells. These data provide an explanation for the increase in fracture rates observed by pediatricians in obese adolescents, and suggest that pediatric obesity increases the long-term risk of osteoporosis in adulthood.

2. Early diet is an important factor in attaining maximal bone mass in adulthood (known as peak bone mass). The relationship between obesity, diet, and bone formation is not well understood. Investigators at the Arkansas Children's Nutrition Center in Little Rock, AR, have identified two potential explanations for the effects of early diet on bone formation. One explanation involves three proteins (Wnt, BMP, and Runx2) that control bone formation. The actions associated with these proteins are blocked by high fat diets and obesity, which decrease bone formation, but are stimulated by blueberries and soy products, which increase bone mass. The second explanation involves two other proteins (RANKL and RANK) that control bone breakdown. These proteins are blocked by berries and soy, but stimulated by obesity. Thus, early diet can influence risk of osteoporosis in old age by increasing bone formation and reducing bone breakdown, resulting in higher peak bone mass as adults, a process that initiates in childhood.

3. Maternal obesity impairs fat metabolism and energy expenditure in offspring. It has been suggested that the environment the fetus develops in during pregnancy may help determine later body composition. Investigators at the Arkansas Children's Nutrition Center in Little Rock, AR, have shown that maternal obesity prior to conception and during pregnancy leads to the development of obesity and associated diseases such as insulin resistance and fatty liver in offspring. ACNC scientists found that offspring of obese mothers had decreased energy expenditure, were less able to burn fat for energy, and overall acquired more body fat. Liver cell mitochondria are sites for fat burning to take place, and results indicate that proteins that are directly or indirectly involved in using fat for energy were suppressed. Results suggest that defects in mitochondrial development contribute to the development of metabolic abnormalities and obesity in offspring from obese mothers.

4. Soy products found to alter drug metabolism. Although soy consumption has been thought to alter metabolism and effectiveness of many drugs, the mechanism by which this occurs is unknown. Investigators at the Arkansas Children's Nutrition Center in Little Rock, AR, found that soy consumption promotes the interaction of a protein (a "transcription factor" known as PXR) and the gene that is responsible for the production of a protein enzyme (known as CYP3A1) that metabolizes many drugs. Soy formulas are consumed by over one million American infants each year, and these data from animal studies suggest infants fed soy formula may experience problems with effectiveness of some medications.

5. Consuming blueberries during early development increases peak bone mass in adults and reduces osteoporosis risk. Peak bone mass is usually achieved during age 20-30 and declines thereafter with age to a point where osteoporosis may develop and fracture risk is increased. Risk of osteoporosis is particularly great in women, where bone loss after menopause is further increased due to loss of estrogens. Researchers at the Arkansas Children's Nutrition Center in Little Rock, AR, found that feeding diets supplemented with blueberries to female rats only during the period from weaning until puberty results in increased peak bone mass and protects against bone loss in adults. These data are the first demonstration that early diet can play a critical role in maximizing bone mass as adults. The results suggest that blueberries consumed before puberty may help reduce osteoporosis risk in later life.

6. Interplay between early obesity, soy foods, and breast cancer development. Breast cancer risk is thought to be greater in obese women, and this is associated with increased mammary fat content. Yet it is not clear whether and how obesity in childhood may lead to increased incidence of breast cancer later in adult life. Scientists at the Arkansas Children's Nutrition Center, Little Rock, AR, discovered that offspring from mothers who ate soy-containing diets during pregnancy and lactation had smaller fat cells in their developing mammary glands. This decrease in fat cell size is accompanied by increased production of proteins (known as adipokines) that promote the action of another protein (known as estrogen receptor beta) in mammary epithelial cells to protect against breast cancer development. These data suggest that early soy consumption can lower breast cancer risk through effects on "bioactive factors" in mammary fat.

7. Rice protein isolate prevents heart disease by increasing antioxidant defenses. Heart disease is the leading cause of mortality in the US population and is related to clogging of the arteries. Early diet is an important factor in determining the risk of arterial blockage. Investigators at the Arkansas Children's Nutrition Center in Little Rock, AR, showed that lifetime feeding of rice protein isolate (RPI) (protein isolated from rice, which is in widespread use in processed foods) can prevent heart disease in mice with a predisposition for artery blockage. This appears to be caused by increasing cellular defenses against oxidative stress. These data suggest that RPI contain dietary factors that are heart protective and could be used to enrich processed foods or developed into new drugs or dietary supplements for prevention of coronary artery disease.

8. The anti-inflammatory properties in blueberries help protect against heart disease. Blueberries have been reported to reduce coronary artery disease in mice. Investigators at the Arkansas Children's Nutrition Center in Little Rock, AR, studied the molecular mechanisms underlying this protective effect and found that white blood cells from mice fed blueberries were less able to make certain inflammatory factors, such as the cytokines TNF alpha and IL-6. These data suggest that blueberries contain dietary benefits with potent anti-inflammatory properties and that early berry consumption can protect against heart disease and other inflammatory diseases.

9. Improved procedures for analysis of tissue fatty acid composition. Investigators at the Arkansas Children's Nutrition Center in Little Rock, AR, developed improved methods to assess tissue fatty acid composition (components of triglycerides and phospholipids). They used these methods in rats with abnormal liver fat accumulation, a condition that is common in childhood obesity (known as NASH), to show the importance of increased polyunsaturated fatty acid composition of liver triglycerides in progression of liver injury. This technology will allow researchers greater insight into the effects of diet on liver fat metabolism and storage, and potentially lead to improved management of obese children with liver storage disorders.

Review Publications
Simmen, F.A., Mercado, C.P., Zavacki, A., Huang, S.A., Greenway, A.D., Kang, P., Bowman, M.T., Prior, R.L. 2010. Soy protein diet alters expression of hepatic genes regulating fatty acid and thyroid hormone metabolism in the male rat. Journal of Nutritional Biochemistry. 21(11):1106-1113.

Wu, X., Tong, Y., Shankar, K., Baumgardner, J.N., Kang, J., Badeaux, J., Badger, T.M., Ronis, M.J. 2011. Lipid fatty acid profile analyses in liver and serum in rats with nonalcoholic steatohepatitis using improved gas chromatography-mass spectrometry methodology. Journal of Agricultural and Food Chemistry. 59(2):747-754.

Marecki, J.C., Ronis, M.J., Shankar, K., Badger, T.M. 2011. Hyperinsulinemia and ectopic fat disposition can develop in the face of hyperadiponectinemia in young obese rats. Journal of Nutritional Biochemistry. 22(2):142-152.

Prior, R.L. 2010. Anthocyanins and weight loss. CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources. 5(29):1-9.

Chen, J., Lazarenko, O.P., Wu, X., Tong, Y., Blackburn, M.L., Shankar, K., Badger, T.M., Ronis, M.J. 2010. Obesity reduces bone density through activation of PPAR Gamma and suppression of Wnt/Beta-Catenin in rapidly growing male rats. PLoS One. 5(10):e13704.

Ronis, M.J., Chen, Y., Liu, X., Blackburn, M., Shankar, K., Landes, R.D., Fang, N., Badger, T.M. 2011. Enhanced expression and glucocorticoid-inducibility of hepatic Ccytochrome P450 3A involve recruitment of the pregnane-x-receptor to promoter elements in rats fed soy protein isolate. Journal of Nutrition. 141(1):10-16.

Khanal, R.C., Rogers, T.J., Wilkes, S., Howard, L.R., Prior, R.L. 2010. Effects of dietary consumption of cranberry powder on metabolic parameters in growing rats fed high fructose diets. Food and Function. 1(1):116-123.

Ronis, M.J., Hennings, L., Stewart, B., Basnakian, A.G., Apostalov, E.O., Albano, E., Badger, T.M., Petersen, D.R. 2011. Effects of long term ethanol administration in a rat total enteral nutrition model of alcoholic liver disease. American Journal of Physiology - Gastrointestinal and Liver Physiology. 300(1):G109-G119.

Chen, J., Lazarenko, O.P., Wu, X., Kang, J., Shankar, K., Blackburn, M.L., Badger, T.M., Ronis, M.J. 2010. Dietary induced serum phenolic acids promote bone growth via p38 MAPK / Beta-Catenin Canonical Wnt signaling. Journal of Bone and Mineral Research. 25(11):2399-2411.

Burris, R.L., Xie, C., Thampi, P., Wu, X., Melnyk, S., Nagarajan, S. 2010. Dietary rice protein isolate attenuates atherosclerosis in apoE-deficient mice by upregulating antioxidant enzymes. Atherosclerosis. 212(1):107-115.

Chen, J., Lazarenko, O.P., Shankar, K., Blackburn, M.L., Lumpkin, C.K., Badger, T.M., Ronis, M.J. 2011. Inhibition of NADPH oxidases prevents chronic ethanol-induced bone loss in female rats. Journal of Pharmacology and Experimental Therapeutics. 336(3):734-742.

Su, Y., Shankar, K., Rahal, O., Simmen, R.C. 2011. Bidirectional Signaling of Mammary Epithelium and Stroma: Implications for Breast Cancer—Preventive Actions of Dietary Factors. Journal of Nutritional Biochemistry. 22(7):605-611.

Yu, S., Peng, M., Ronis, M.J., Badger, T.M., Fang, N. 2010. Analysis of polar lipids in the serum from fats fed shiitake by liquid chromatography-mass spectrometry/mass spectrometry. Journal of Agricultural and Food Chemistry. 58(24):12650-12656.

Xie, C., Ng, H., Nagarajan, S. 2011. OxLDL or TLR2-induced cytokine response is enhanced by oxLDL-independent novel domain on mouse CD35. Immunology Letters. 137(1):15-27.

Prior, R.L., Fan, E., Ji, H., Howell, A., Nio, C., Payne, M.J., Reed, J. 2010. Multi-laboratory validation of a standard method for quantifying proanthocyanidins in cranberry powders. Journal of Agricultural and Food Chemistry. 90(9):1473-1478.

Xie, C., Kang, J., Burris, R., Ferguson, M.E., Schauss, A.G., Nagarajan, S., Wu, X. 2011. Acai juice attenuates atherosclerosis in apoe deficient mice through antioxidant and anti-inflammatory activities. Atherosclerosis. 216(2):327-333.

Kang, J., Xie, C., Li, Z., Nagarajan, S., Schauss, A.G., Wu, T., Wu, X. 2011. Flavonoids from acai (euterpe oleracea mart.) Pulp and their antioxidant and anti-inflammatory activities. Journal of Food Chemistry. 128(1):152-157.

Ronis, M.J., Mercer, K., Chen, J. 2011. Effects of Nutrition and Alcohol Consumption on Bone Loss. Osteoporosis Report. 9(2):53-59.

Borrengasser, S.J., Lau, F., Kang, P., Blackburn, M.L., Ronis, M.J., Badger, T.M., Shankar, K. 2011. Maternal obesity during gestation impairs fatty acid oxidation and mitochondrial SIRT3 expression in rat offspring at weaning. PLoS One. 6(8):e24068. doi:10.1371/journal.pone.0024068.

Rahal, O., Simmen, R.C. 2011. Paracrine-acting adiponectin promotes mammary epithelial differentiation and synergizes with genistein to enhance transcriptional response to estrogen receptor beta signaling. Endocrinology. 152(9):3409-3421.

Zhang, J., Lazarenko, O.P., Blackburn, M.L., Shankar, K., Badger, T.M., Ronis, M.J., Chen, J. 2011. Feeding Blueberry Diets in Early Life Prevent Senescence of Osteoblasts and Bone Loss in Ovariectomized Adult Female Rats. PLoS One. 6(9):e24486. doi:10.1371/journal.pone.0024486.

Simmons, C.D., Pabona, J.P., Heard, M.E., Friedman, T., Michael, S., Godley, A.L., Simmen, F.A., Burnett, A., Simmen, R.C. 2011. Krüppel-Like factor 9 loss-of-expression in human endometrial carcinoma links altered expression of growth-regulatory genes with aberrant proliferative response to estrogen. Biology of Reproduction. 85(2):378-385.

Zhou, H., Xie, C., Jian, R., Kang, J., Li, Y., Zhuang, C., Yang, F., Lai, L., Wu, T., Wu, X. 2011. Biflavonoids from caper (capparis spinosa l.) Fruits and their effects in inhibiting nf-kappa b activation. Journal of Agricultural and Food Chemistry. 59(7):3060-3065.

Zhou, H., Jian, R., Kang, J., Huang, X., Li, Y., Zhuang, C., Yang, F., Zhang, L., Fan, Z., Wu, T., Wu, X. 2010. Anti-inflammatory effects of caper (capparis spinosa l.) Fruit aqueous extract and the isolation of main phytochemicals. Journal of Agricultural and Food Chemistry. 58(24):12717-12721.

Chiu, L., Zhou, X., Burke, S., Wu, X., Prior, R., Li, L. 2010. The purple cauliflower arises from activation of a myb transcription factor. Journal of Plant Physiology. 154(3):1470-1480.

Khanal, R., Howard, L., Prior, R.L. 2010. Effect of heating on the stability of grape and blueberry pomace procyanidins and total anthocyanins. Food Research International. 43(5):1464-1469.

Last Modified: 07/25/2017
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