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Research Project: Impact of Early Dietary Factors on Child Development and Health

Location: Arkansas Children's Nutrition Center

2016 Annual Report

Overall objective is to gather evidence about important environmental factors that have long-term consequences on child development/health, and their health as children become adults. 1: Continue Beginnings study, longitudinal study of growth/development/body composition in infants breast-fed or fed soy/cow milk formula. 2: Determine if soy feeding affects estrogen receptor beta using chromatin immunoprecipitation analysis; gene deletion studies in appropriate animal models to ascertain if soy protein affects reproductive development/metabolism/body composition via activation of ERbeta-mediated signaling. 3: Determine body composition/metabolism of prepubertal pigs fed breast milk/milk formula/soy formula as neonates, then weaned onto either low or high fat diet. Compare data with body composition/metabolism in children age 5 from Beginnings Study. 4: Determine effects of early diet in pig model on gut-associated lymphoid tissue development/function; ... 5: Characterize effects of neonatal diet on composition of intestinal microbiota, Collect urine/fecal samples from Beginnings Study infants/children at 3/6/9/12 months and yearly thereafter. 6: Determine if feeding blueberries (BB) and other fruits/vegetables containing phenolic acid (PA) chlorogenic acid (CA) or treatment with CA metabolite hippuric acid stimulate bone growth in rodent model; examine role of G-coupled receptor protein GPR109A as potential mediator of PA effects on bone. 7: Perform peripheral quantitative computerized tomography to study bone morphology; measure urine/serum bone turnover markers in lean/obese prepubertal children with/without additional symptoms of insulin resistance. 8: Determine ability of diets containing BB to block obesity-induced impairment in bone quality/strength in weaning rats; determine method of activiation in underlying mechanisms by which this occurs. Determine if bone turnover markers in urine/serum of obese children are improved after short-term intervention with BB-containing diets. 9: Determine if toll-like receptor/early response protein-1 signaling is mediating embryonic/placental inflammation and epigenetic dysregulation in offspring due to maternal obesity in rodent models/human subjects. 10: Characterize effect of maternal obesity on programming offspring's metabolism and risk of obesity later in life in the Glowing study. 11: Determine if interventions prior to/during pregnancy that alter maternal hyperinsulinemia, gastrointestinal microbiome and/or inflammation prevent obesity-induced metabolic programming in animal models. 12: Determine if reprogramming of offspring energy metabolism/mitochondrial function can occur by promoting neonatal physical activity or dietary factors in rodent models. 13: Determine effects of early diet on neurocognitive development by completing neurophysiological/behavioral aspects of Beginnings study. 14: Determine effects of diet composition, meal pattern/frequency on brain development/function, and behavioral dynamics important for learning in well-characterized lean/obese school children. 15: Characterize how neurocognitive functions associated with obesity can be improved by physical activity.

Studies will focus on the various dietary factors found in foods commonly consumed by children, such as breast milk, infant formulas, fruits, grain, 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 development of 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, liver, adipose tissue, pancreas, gastrointestinal tract, bone, skeletal muscle and the immune system; 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, The Beginnings Study, which is a longitudinal study of breast-fed, milk formula-fed, and soy formula-fed children from birth through puberty, will evaluate growth, development, body composition, metabolism, bone development, and immune system development and function. Animal models such as the neonatal pig will be utilized to explore molecular mechanisms underlying the effects of early dietary exposures. Rodent models will be used to understand the parental epigenetic transmission of the effects of maternal obesity and high fat feeding to future generations and underlying molecular, biochemical, and endocrine mechanisms, in the offspring. These studies will be translated in an ongoing longitudinal clinical study of infant body composition in children of lean and overweight women (The Glowing Study). 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). Children (infants, toddlers, and school-aged youths) will be studied to evaluate the effects of infant diet (specifically, breast-milk and a variety of infant formulas) on morphological, neurophysiological, behavioral, and cognitive development in infants and children. Nutritional status assessments, anthropometric measurements, body composition, energy metabolism, physical activity fitness, urine and blood analysis, and measures of brain structure (MRI imaging), psychological and behavioral status (standardized testing), neuropsychological, and cognitive measures will be obtained and analyzed. The effects of diet composition, meal patterns, meal frequency, physical activity, and body composition on brain function, behavioral dynamics, learning, and school performance will be assessed in normal weight and overweight/obese school children using validated survey instruments and state-ofthe-art research equipment.

Progress Report
Studies that examine maternal-infant cohorts over many years, from birth onward, provide critical information related to the long-term impact of infant diet, maternal obesity, post-weaning diet and other factors on the body's systems and development into childhood and beyond. The Arkansas Children's Nutrition Center (ACNC) is uniquely-positioned to address this, and has made strong progress toward understanding the basis of diet- and maternal obesity-associated changes in offspring's body fat, childhood obesity risk, bone health, gut and immune functions, and brain/behavior development. For the "Dietary Factors in Development" Project: The Beginnings Study follows growth, body composition and brain development from birth through age 6 years of 600 children who were fed breast-milk, soy-based infant formula or cow's milk-based formula: it is the world's largest prospective, longitudinal study of its kind. This year, there were 117 study visits completed. Results to date have not revealed any adverse effects of soy-based infant formula feeding in children. This is important since there has been some controversy over the years with respect to potential "estrogen-like" effects of soy. Complementary studies in piglet models explore the tissue-level relationship between soy and estrogen receptor signaling pathways in key estrogen-responsive reproductive organs. In rat models of estrogen-responsiveness, estradiol (an estrogen) caused hormone-specific uterine gene expression changes, not observed with soy protein diets supplemented with estradiol. Moreover, soy food components may have anti-inflammatory effects which are potentially beneficial to promote liver health: soy protein feeding protected against liver injury and tumors in mice receiving a liver challenge (high fat diet and alcohol). These findings provide a rationale to test if soy could help prevent accumulation of excess liver fat in populations at high risk (i.e., pediatric obesity). For the "Effects of Early Diet on Gastrointestinal Development and Function" Project: Breastfeeding is associated with a variety of positive health outcomes and is recommended exclusively for the first 6 months of life; however, 50-70% of infants in the U.S. are formula-fed. To test whether immune system development and function are significantly influenced by postnatal diet, piglets (an animal model of infant gut and immune development) were fed formula until day 21 and compared to a breastfed sow-fed group. In formula-fed animals the size of the gastrointestinal lymphoid follicles (a major gut immune tissue) was significantly lower, proteins involved in membrane integrity were decreased, and inflammatory molecules increased. These outcomes correlated with changes in the natural population of gut microbes (bacteria) referred to as the "microbiome." The experiments provide new evidence of molecular and tissue-level events that could explain how breastfeeding promotes immune system development, potentially relevant to childhood food allergies and infection. For the "The Role of Dietary Factors in Skeletal Development" Project: Bone health and osteoporosis risk in adults can be influenced by childhood diet, exercise and obesity status. It remains to be determined the full suite of dietary factors that can influence bone turnover and integrity. ACNC investigators discovered that specific components of blueberries improve bone health, and have ongoing studies to validate the specific target of this bone-promoting activity (a receptor, GPR109A). Investigators have developed a mouse model in which GPR109A is absent and determined the effects on normal bone development. Studies are underway to understand if the bone growth effects of blueberries (or specific blueberry components such as 3-(3-hydroxyphenyl) propionic acid) are lost in these mice. In human studies looking at the impact of obesity on bone health, the bone quality and quantity in obese and lean children is being studied. More than 80 children qualified for the study. Another important area of research is bone and infant diet. Taking advantage of the Beginnings Study, investigators continue to examine the effect of the three early infant diets (especially soy, thought to have effects on bone) on skeletal development and bone strength in 5 year old children. This year, 37 children were enrolled. For "Maternal Programming of Offspring Metabolism and Obesity" and "Interventions to Mitigate Maternal Obesity-Associated Programming" Projects: Studies focus on the intergenerational transmission of obesity from mother to offspring. Key features of this "programming" include alterations in fetal/offspring fat metabolism, commitment and differentiation of stem cells, and even placenta inflammation and development. Studies are identifying modifying factors that can be targeted to prevent disease and improve functional outcomes in children: i.e., maternal nutrition, physical activity and body composition (lean vs. fat). The Glowing Study is the first prospective long-term study testing if obesity during pregnancy produces a fetal environment and DNA changes that influence offspring developmental programming. This year, 743 infant and children visits were completed and 89 mother-children pairs graduated from the study (age 2 years). To determine if DNA modifications are involved in maternal obesity-associated differences in children's outcomes, placenta samples from the entire Glowing cohort have been analyzed for DNA loci-specific imprinted genes. Ongoing studies are determining if these epigenetic changes (DNA methylation and histone modification to the chromosome structure) are associated with mother and child body weight and metabolic outcomes. The Expecting Study investigates if physical activity in pregnancy improves maternal metabolic health, in turn ameliorating effects of maternal obesity-associated programming on offspring. This year, 145 study visits were conducted. Preliminary results indicate that exercise is successfully improving fitness and lowering gestational weight gain. In complementary rodent studies, the effects of voluntary wheel running on offspring and placental adaptations are tested. In addition, the effect of early-life post-weaning exercise on adult weight gain and metabolic end-points in rodents is currently under study. The human and animal study results will provide a scientific evidence base for clinical recommendations related to exercise in pregnancy. Male offspring of obese mice show remarkable increases in obesity, hepatic inflammation and metabolic changes. New studies are finding that stem cells or pre-fat cells from offspring of obese female mice have impaired ability to differentiate into "calorie-burning" brown fat. In addition, profiling of the natural intestinal microbial population (microbiome) revealed persistent changes in the gut microbiome associated with maternal and offspring high-fat diets, a potential mechanism contributing to obesity and metabolism differences. Microbiome analysis of fecal microbiota from children in the Glowing study is underway to see if maternal obesity also remodels human offspring microbiome. For "Dietary Influences on Psychological and Neuropsychological Development and Function in Children" Project: The ongoing longitudinal Beginnings study tracks neurodevelopment and behavior in parallel with other outcomes (see description above) through 6 years of age in 600 children. This year assessments were made on 99 participants during 117 visits, and data collection for participants through age 5 years is complete. Notably, 47 had their 6 year visits, bringing the number of subjects that have completed the full study protocol to 339. The study is generating first-ever normative data on childhood brain development and function, and documenting the influence of different infant diets on these measures. The team has begun to analyze two large datasets from resting brain recordings that will provide novel diet-related longitudinal developmental information regarding brain electrical activity and cardiovascular regulation. One dataset, focused brain regions important for attention and memory functions, includes data from 487 children obtained over 2044 visits, and will chart the development from 1 to 5 years. Recent analyses indicate that brain electrical activity reflecting relationships fundamental to language development and general cognitive function is influenced by the diet children were fed as infants. Another line of work, using data from 436 children and 1224 visits, will extend our center's published studies documenting the development of heart rate regulation to years 3 through 5. Other ongoing studies address the question of whether variations in infant diet or obesity can be related to differences in brain structure and activities of neuronal connections. These studies apply advanced non-invasive imaging [MRI (Magnetic Resonance Imaging) and fMRI (functional MRI)] and electrophysiological (high density recordings of brain electrical activity) technologies to evaluate measures of brain activity at rest. Such approaches are being applied to test for effects of early life diet (Beginnings Study), maternal obesity during pregnancy (Glowing Study), exercise and metabolic health of the mother during pregnancy (Expecting Study), and in comparisons of lean and obese children.

1. Obesity leads to ovarian inflammation. Obesity has been linked to impaired reproductive function in women of child bearing age, and maternal obesity is associated with higher risk that offspring will develop obesity and related metabolic disorders. These phenomena may involve early molecular events related to the environment around the mother's egg (oocyte) even before conception, yet very few studies have investigated the effect of obesity on ovarian function. Investigators at the Arkansas Children's Nutrition Center in Little Rock, Arkansas have examined ovarian gene expression of overfed compared to normal weight rats, and demonstrated that obese dams have greater ovarian inflammation. We identified a gene regulator that may be involved in this process, in cells surrounding the oocyte. These findings provide novel evidence that obesity and/or poor metabolic health may negatively impact ovarian function.

2. Maternal obesity reconfigures offspring gut bacteria. A mother's diet and body composition during pregnancy have significant influence on her baby's health later in life. One possibility by which such changes may occur is through changes in the gut microbiome, i.e. the diverse set of bacteria, viruses, and other microbes in the intestinal tract, known to have profound effects on host heath. Investigators at the Arkansas Children's Nutrition Center in Little Rock, Arkansas, have utilized bacterial genomic sequencing in mice born to either lean or obese mothers, and found that offspring from the latter display an altered gut microbiome that was also impacted by maternal diet and persisted into late adulthood. The findings suggest that maternal obesity alters the structure of the gut microbiome and thus could contribute to increased propensity to obesity and metabolic disease in their offspring.

3. Mother's obesity impairs conversion of white fat into 'thermogenic' brown/beige fat. Not all fat is created equal: a type of fat tissue called 'brown or beige fat' with high capacity to generate heat and burn calories is positively associated with lower weight. New research at the Arkansas Children's Nutrition Center in Little Rock, Arkansas suggests that the ability to generate brown fat-like cells under specific conditions such as exercise, cold exposure and certain chemical activators in offspring is influenced by maternal obesity influenced the ability of offspring to generate brown/beige fat. Stem cells isolated from offspring of obese mice also showed impaired differentiation into brown/beige fat cells, suggesting a defect in developmental pathways. These findings indicate that altered metabolism and increased obesity risk in offspring of obese mice may be related in part to fat cell differentiation into calorie-burning brown fat.

4. Programming the risk of offspring liver disease by maternal obesity. A large number of young adults are at high risk of developing fatty liver and other progressive disorders due to obesity and sedentary lifestyle, but increasing evidence points to factors in the womb that can help drive offspring obesity and related disorders. Researchers at the Arkansas Children's Nutrition Center in Little Rock, Arkansas used cutting-edge methodology to monitor the expression of genes and examine decorative marks on the DNA (methylation, a type of "epigenetics" that can regulate gene expression) in response to diets promoting liver dysfunction in mice. Offspring of obese mice had greater inflammation and progression to liver fibrosis, along with changes in methylation in specific pathways thought to be involved in these processes. These findings strongly suggest that maternal obesity might detrimentally alter the ability of the offspring's liver to cope with dietary and other challenges that promote inflammation. These results from a rodent model support the development of dietary or exercise strategies that ameliorate the effects of maternal obesity in order to promote liver health in at-risk children.

5. A novel link between obese fat tissue and cardiovascular function. Obesity is associated with increased risk of cardiovascular disease, so identifying the pathways involved is critical to develop preventive dietary or other strategies. Recent studies suggest that early growth response 1 (Egr-1), a gene regulating inflammation, is increased in fat tissues of obese animals and humans, but its role in linking obesity and cardiovascular disease has been unclear. Using mice lacking Egr-1, researchers at the Arkansas Children's Nutrition Center in Little Rock, Arkansas demonstrated that many genes involved in the inflammatory response, blood vessel development and fat differentiation were altered by the absence of Egr-1, and these outcomes were more apparent in males. Mice lacking Egr-1 had blood vessels with reduced contraction capacity, illustrating that Egr-1 plays a role in blood vessel function. Since many vessels in the body are surrounded by fat tissue, these results raise the possibility that Egr-1 in this perivascular fat participates in the link between obesity and cardiovascular disease risk.

6. Formula feeding during the neonatal period alters the immune system. Breastfeeding is associated with a variety of positive health outcomes in children and is recommended exclusively for the first 6 months of life; however, 50-70% of infants in the U.S. are formula-fed. Whether or not exclusive or partial formula feeding impacts the immune system development remains an open question, prompting scientists at the Arkansas Children's Nutrition Center in Little Rock, Arkansas to study this issue in piglets fed formula (soy- or dairy-based) or breastfed (sow) for 19 days. It was discovered that formula feeding led to significant differences in the protective immune system located in the gut, including lower size of lymphoid follicles (regions that control "immune education" to external pathogens), higher expression of inflammatory molecules, down-regulation of growth factor and anti-inflammatory molecule expression, and decreased GI markers of membrane permeability. Formula feeding-associated changes were accompanied by shifts in the bacterial microbiome (bacteria that naturally reside in the GI). These studies firmly establish that neonatal diet in the first weeks following birth in piglets has profound effects on immunity and inflammation, raising the possibility that formulas that better mimic mother's milk could optimize newborn immune system function.

7. Gender differences in brain language comprehension at 3 years are related to infant diet. The ability to associate images with words is essential for language comprehension and cognitive function and begins to emerge in toddlers, but it is not known if this early semantic development is modulated by infant diet and gender. Scientists at the Arkansas Children's Nutrition Center in Little Rock, Arkansas studied these relationships in 3 year old children who were breast-fed (BF), or fed milk formula (MF) or soy formula (SF) as infants by recording EEG gamma activity as they viewed images of familiar objects/animals while hearing single non-words or words that matched or didn't match the images—a measure of associative memory strength. For all groups the EEG gamma amplitude was lower following non-words—indicating unrecognized image-word associations—but was greater for SF boys than other groups, and for BF girls compared to other girls following. These results provide the first evidence that early infant diet-gender interactions contribute to the development of neural networks involved in language processing in children, and these early relationships may shape gender-related semantic skills later in development.

8. Childhood obesity is associated with increased brain white matter and some studies have shown that childhood obesity can alter brain cognitive function, but this is controversial and little is known about brain development in obese, but otherwise healthy children. Previously, it was discovered that obese children have reduced brain grey matter (which is a contributor to cognitive function). Scientists at the Arkansas Children's Nutrition Center in Little Rock, Arkansas used advanced neuroimaging methods to evaluate the volume and microstructures of a different part of the brain-white matter (myelinated fibers which provide pathways of communication among neural networks responsible for information processing) in healthy 8-10 year old children who were either normal weight or obese. Obese children had significantly more white matter than normal weight children in brain regions involved in the regulation of attention and working memory, and altered water diffusion parameters that track white matter microstructure in tracts involving projection and association. These findings identify novel differences in brain structural features in obese children, and provide new insights into brain developmental variations that may precede those associated with adult obesity.

9. Pre-adolescents breastfed as infants show greater brain gray matter and better cognitive function. The basis for commonly-reported differences in cognitive function of breastfed and formula-fed children has not been determined. Scientists at the Arkansas Children's Nutrition Center in Little Rock, Arkansas used advanced neuroimaging methods to relate brain gray matter volume and cognitive performance on visual memory and language rhyming tasks in healthy 8-10 year old children, who were either breastfed or milk formula-fed as infants. Gray matter contains networks of neurons that are responsible for information processing in the brain. Breastfed children showed more gray matter in task-related brain regions, greater activation of these areas during tasks, and better task performance. These findings increase our understanding of brain structural features contributing to differences between breastfed and formula-fed children in cognitive function, and suggest that infant diets have long-term influences on children’s brain development and function later in life.

10. Diet-associated changes in gut bacteria (microbiome) impact kidney and liver function. The microbes that live in the intestine (making up the "gut microbiome") are sensitive to diet, type of delivery at birth, and environmental exposures. The microbiome has a profound influence on the body's tissues and organs, but very little is known about the myriad of signals and pathways involved. Scientists at the Arkansas Children's Nutrition Center, in collaboration with UC Davis, discovered that diets rich in resistant starch (RS) fiber can modify select gut microbes that help regulate protein metabolism in the host. In one study in rats, prevention of kidney disease was attributed to lowered body nitrogen load by RS-modified gut bacteria, and in a different study the gut microbiome changes corresponded to reduced liver amino acids. These results provide new evidence to explain mechanisms by which dietary fiber, and other modifiable dietary components that alter the microbiome, influence health.

11. An epigenetic map of placental cell formation. The placenta is the earliest organ of the baby to develop in the womb, and specific cells in the placenta create the barrier between mother and baby through which all signals and nutrients are exchanged. Development of this barrier is critical to a successful pregnancy and ultimately, infant development and function. Using cutting-edge approaches to examine the genome in placenta (the aggregate of all DNA and genes), researchers at the Arkansas Children's Nutrition Center in Little Rock, Arkansas examined the process by which this barrier is formed and sustained. The studies revealed involvement of several novel pathways required for placental development, including a unique epigenetic process (histone acetylation, or the modification of the DNA structure). Epigenetics processes can be influenced by several factors including diet and maternal health, so these results raise the possibility that optimizing nutrition and health in expecting mothers has measurable effects on placental development, hence impacting lifelong health of the child.


Review Publications
Saben, J., Thakali, K.M., Lindsey, F.E., Zhong, Y., Badger, T.M., Andres, A., Shankar, K. 2015. Distinct adipogenic differentiation phenotypes of human umbilical cord mesenchymal cells dependent on adipogenic conditions. Experimental Biology and Medicine. 239(10):1340-1351.
Ou, X., Andres, A., Pivik, R.T., Cleves, M.A., Badger, T.M. 2015. Brain gray and white matter differences in healthy normal weight and obese children. Journal of Magnetic Resonance Imaging. 42(5):1205-1213.
Mccoin, C.S., Piccolo, B.D., Knotts, T.A., Matern, D., Vockley, J., Gillingham, M.B. 2016. Unique plasma metabolomic signatures of individuals with inherited disorders of long-chain fatty acid oxidation. Journal of Inherited Metabolic Disease. 39(3):399-408.
Caro, A.A., Bell, M., Ejiofor, S., Zurcher, G., Petersen, D.R., Ronis, M.J. 2014. N-acetylcysteine inhibits the up-regulation of mitochondrial biogenesis genes in livers from rats fed ethanol chronically. Alcoholism: Clinical and Experimental. 38(12):2896-2906.
Chen, J. 2016. Effect of diet-induced maternal obesity on fetal skeletal development. In: Watson, R.R., Mahadevan, D., editors. Handbook of Nutrition and Diet in Therapy of Bone Diseases. The Netherlands: Wageningen Academic. p. 67-79.
Ou, X., Andres, A., Pivik, R.T., Cleves, M.A., Snow, J.H., Ding, Z., Badger, T.M. 2015. Voxel-based morphometry and fMRI revealed differences in brain gray matter in breastfed and milk formula–fed children. American Journal of Neuroradiology. 37:713-719. doi: 10.3174/ajnr.A4593.
Kieffer, D., Piccolo, B., Vaziri, N., Liu, S., Lau, W., Khazaeli, M., Nazertehrani, S., Moore, M., Marco, M., Martin, R. 2016. Resistant starch alters gut microbiome and metabolomics profiles concurrent with amelioration of chronic kidney disease in rats. American Journal of Physiology - Renal Physiology. 310(9):857-871. doi: 10.1152/ajprenal.00513.2015.
Piccolo, B., Graham, J., Stanhope, K., Fiehn, O., Havel, P., Adams, S.H. 2016. Plasma amino acid and metabolite signatures tracking diabetes progression in the UCD-T2DM rat model. American Journal of Physiology - Endocrinology and Metabolism. 310(11):958-969. doi: 10.1152/ajpendo.00052.2016.
Yeruva, L., Spencer, N.E., Saraf, M.K., Hennings, L., Bowlin, A.K., Cleves, M., Mercer, K., Chintappalli, S.V., Shankar, K., Rank, R., Badger, T.M., Ronis, M.J. 2016. Formula diet alters small intestine morphology, microbial abundance and reduces VE-cadherin and IL-10 expression in neonatal porcine model. BioMed Central (BMC) Gastroenterology. 16:40. doi: 10.1186/s12876-016-0456-x.
Gomez-Acevedo, H. 2015. Revisiting separation properties of convex fuzzy sets. Journal of Intelligent & Fuzzy Systems. 29(2):845-849. doi: 10.3233/IFS-151613.
Porter, C., Herndon, D., Borsheim, E., Bhattarai, N., Chao, T., Reidy, P.T., Rasmussen, B.B., Andersen, C.R., Suman, O.E., Sidossis, L.S. 2016. Long-term skeletal muscle mitochondrial dysfunction is associated with hypermetabolism in severely burned children. Journal of Burn Care and Rehabilitation. 37(1):53-63. doi: 10.1097/BCR.0000000000000308.
Ruebel, M., Shankar, K., Gaddy, D., Lindsey, F., Badger, T.M., Andres, A. 2016. Maternal obesity is associated with ovarian inflammation and up-regulation of early growth response factor 1. American Journal of Physiology - Endocrinology and Metabolism. 311(1):E269-E277. doi: 10.1152/ajpendo.00524.2015.
Ronis, M.J., Gomez-Acevedo, H., Blackburn, M.L., Cleves, M.A., Singhal, R., Badger, T.M. 2016. RNA-sequencing data analysis of uterus in ovariectomized rats fed with soy protein isolate,17B-estradiol and casein. Data in Brief. 7:1491-1496.
Mercer, K.E., Pulliam, C., Hennings, L., Lai, K., Cleves, M., Jones, E., Drake, R.R., Ronis, M.J. 2016. Soy protein isolate protects against ethanol mediated tumor progression in diethylnitrosamine treated male mice. Cancer Prevention Research. 9(6):466-475. doi: 10.1158/1940-6207.CAPR-15-0417.
Bedinger, D.H., Adams, S.H. 2015. Metabolic, anabolic, and mitogenic insulin responses: A tissue-specific perspective for insulin receptor activators. Molecular and Cellular Endocrinology. 415:143-156. doi: 10.1016/j.mce.2015.08.013.
Shankar, K., Kang, P., Zhong, Y., Borengasser, S.J., Wingfield, C., Saben, J., Gomez-Acevedo, H., Thakali, K.M. 2015. Transcriptomic and epigenomic landscapes during cell fusion in BeWo trophoblast cells. Placenta. 36(12):1342-1351.
Panasevich, M.R., Morris, E.M., Chintapalli, S.V., Wankhade, U.D., Shankar, K., Britton, S.L., Koch, L.G., Thyfault, J.P., Rector, R.S. 2016. Gut microbiota are linked to increased susceptibility to hepatic steatosis in low aerobic capacity rats fed an acute high fat diet. American Journal of Physiology - Gastrointestinal and Liver Physiology. 311(1):G166-G179. doi: 10.1152/ajpgi.00065.2016.
Ronis, M.J., Gomez-Acevedo, H., Blackburn, M.L., Cleves, M.A., Singhal, R., Badger, T.M. 2016. Uterine responses to feeding soy protein isolate and treatment with 17B-estradiol differ in ovariectomized female rats. Toxicology and Applied Pharmacology. 297:68-80.
Krukowski, R.A., West, D., Dicarlo, M., Shankar, K., Cleves, M.A., Tedford, E., Andres, A. 2016. A behavioral intervention to reduce excessive gestational weight gain. Maternal and Child Health Journal. DOI 10.1007/s10995-016-2127-5.
Wankhade, U.D., Thakali, K.M., Shankar, K. 2016. Persistent influence of maternal obesity on offspring health: Mechanisms from animal models and clinical studies. Molecular and Cellular Endocrinology. doi: 10.1016/j.mce.2016.07.001.
Chintapalli, S.V., Bhardwaj, G., Patel, R., Shah, N., Anishkin, A., Von Rossum, D.B., Patterson, R.L., Adams, S.H. 2015. Molecular dynamic simulations reveal the structural determinants of fatty acid binding to oxy-myoglobin. PLoS One. 10(6):e0128496. doi: 10.1371/journal.pone.0128496.
Hinton, P.S., Shankar, K., Eaton, L.M., Rector, R.S. 2015. Obesity-related changes in bone structural and material properties in hyperphagic OLETF rats and protection by voluntary wheel running. Metabolism. 64(8):905-916. doi: 10.1016/j.metabol.2015.04.004.
Fang, N., Yu, S., Adams, S.H., Ronis, M.J., Badger, T.M. 2016. Profiling of urinary bile acids in piglets by a combination of enzymatic deconjugation and targeted LC-MRM-MS. Journal of Lipid Research. doi:10.1194/jlr.D069831.
Shankar, K. 2015. Reversing gestational undernutrition via kick-starting early growth. Endocrinology. 156(9):3059-3062. doi: 10.1210/en.2015-1625.