Location: Arkansas Children's Nutrition Center2017 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.
Examining maternal-infant cohorts over many years, from the pre-partum period to birth to infancy and childhood, provides critical information related to the long-term impact of infant and child diet, maternal obesity, and other factors on the body's development and on the ability to maintain health. The Arkansas Children's Nutrition Center is uniquely-positioned to make strong progress toward understanding the basis of diet-, exercise-, and maternal obesity-associated changes in offspring's body fat, childhood obesity risk, bone health, gut and immune functions, and brain development. "Dietary Factors in Development" Project: The Beginnings Study follows growth, body composition, bone and brain development from birth-6 yr (600 newborns originally enrolled) fed breastmilk, soy- or dairy milk-based formulas: it is the world's largest prospective longitudinal study of its kind. This year, 75 visits were completed. Despite controversy as to potential "estrogen-like" effects of soy, the Center's research indicates no soy-formula-related differences in the development of reproductive organs in 5 yr olds. Follow-on studies in 14 yr old pre-adolescents will provide a definitive test for the hypothesis that infant soy diet does not impact puberty onset or reproductive function. Other studies explored effects of soy feeding on liver health. Obese children are at high risk of fatty liver which can lead to disease. In a mouse pediatric liver disease model, lipid-derived oxidative stress markers tracked progression of fatty liver inflammatory injury, and dietary soy protein was liver-protective following a high fat, obesity-promoting diet. These findings provide a rationale to test if soy and other liver-protective foods can prevent excess liver fat in pediatric obese populations. "Effects of Early Diet on Gastrointestinal Development and Function" Project: Breastfeeding during the first 6 months is associated with positive health outcomes (i.e., optimal immune system development, allergy reduction); however, 50-70% of U.S. infants are formula-fed. How infant feeding mode impacts health and development remains to be fully elaborated, but may involve changes in the natural population of gut bacteria ("microbiota"), which produce small molecules ("xenometabolites") and other factors that impact body-wide physiology. To study this, 21 d old piglets (model of infant gut/immune development) fed formula vs. sow-fed were compared: in the distal colon, formula reduced microbiota diversity (variety), lowered serotonin, and increased bacterially-derived tryptamine. Dysfunction of serotonin lowers immune system integrity and tryptamine increases histamine which could impact allergy susceptibility. The results suggest that breastfeeding maintains optimal serotonin, tryptamine and histamine status in the lower gut as one mechanism promoting neonatal gut and immune functions. As for small intestine, in the early region (duodenum), it was discovered that sow-fed piglets had more bacterial diversity when compared to piglets fed dairy- or soy-based formula. All diet groups had distinct diet-specific bacteria profiles in the lower region (jejunum-ileum). Many ileum metabolites tracked diet-associated changes in the ileum microbiome. These studies are some of the first to show bioregional changes in the microbiota in response to infant diet, and highlight novel associations between microbiome-host metabolisms. "The Role of Dietary Factors in Skeletal Development" Project: Bone health and adult osteoporosis risk may be influenced by in utero conditions, childhood diet, exercise and obesity. ACNC scientists studied the effects of maternal obesity on bone cell development in both rodents and humans. Maternal obesity increased p53 gene expression (linked to cell senescence (aging)) in fetal osteo-progenitors (cells that can become bone cells); thus, obesity programs bone cell senescence signaling. Bone health can also be influenced by diet. In rats, soy protein isolate (SPI) was found to promote bone formation, and short-term SPI early in life had modest but persistent effects to dampen bone loss in adult females. To address if early life soy intake affects bone in children, bone quality and abundance are being measured by peripheral quantitative CT scans in 5 yr olds from the Beginnings trial, comparing children who were breastfed vs. soy- or dairy-formula fed as infants (24 participants enrolled this year). Other studies are characterizing bone-promoting factors in blueberries. These experiments can inform dietary guidance for infants and children, and are identifying new dietary bioactives with positive effects on bone health. "Maternal Programming of Offspring Metabolism and Obesity" and "Interventions to Mitigate Maternal Obesity-Associated Programming" Projects: Studies focus on the intergenerational transmission of obesity and metabolic health from mother to offspring. Key features of this "programming" include alterations in offspring fat metabolism and fat tissue, commitment and differentiation of stem cells, and placenta inflammation and development. Modifying factors that can be targeted to prevent disease and improve functional outcomes in children are being studied: i.e., maternal nutrition and physical activity. The Glowing Study is the first prospective long-term study testing if obesity in pregnancy influences offspring developmental programming (131 infant/children visits this year; 77 mother-children pairs graduated from the study's 1st phase (age 2 yr)). Maternal, paternal and cord serum blood samples were analyzed for lipid and glucose (blood sugar) panels: these parameters and maternal body fat are being investigated for relationships to offspring body fat growth. To study the mechanisms by which maternal obesity impacts offspring development, a mouse model of high-fat diet-induced obesity was used, showing that male offspring from obese mothers had increased weight gain, liver inflammation and other metabolic changes when fed a high fat diet. This associated with alterations in certain liver DNA regions that were chemically-modified (epigenetic), and with persistent alterations in the gut microbiota. Female offspring showed resistance against postnatal high-fat diet challenge. The studies related to maternal diet-induced obesity indicate that sexual dimorphism in offspring responses: (1) extend to liver pathology and adult offspring microbiome changes; (2) occur early-on (i.e., late-gestation placental inflammation). Some epigenetic regulators reside on sex chromosomes: this is a potential mechanism leading to sex differences. For humans, epigenetic DNA modifications in umbilical cord samples from the Glowing cohort are being studied to determine if specific growth- and body size-related genes associate with mothers' obesity and metabolic health, and if epigenetic changes associate with children's obesity and body fat outcomes. The Expecting Study investigates if physical activity in obese pregnant mothers can ameliorate effects of maternal obesity-associated offspring programming. This year, 37 participants were enrolled (212 study visits). To date, exercise is improving fitness and lowering gestational weight gain; other studies are testing for effects on offspring body composition, fat and protein metabolism. In complementary rodent studies, the effects of maternal voluntary wheel running on offspring weight gain and placental adaptations are being tested. In addition, the effect of early-life (post-weaning) exercise on adult weight gain and metabolism in rodents is studied. Mechanisms that underlie muscle health, performance, and fat/sugar/protein metabolisms are also being evaluated to explain how physical activity associates with positive metabolic health: i.e., studies are examining novel metabolic functions of the muscle protein myoglobin (which gives muscle a red color and ferries oxygen within the cells), and the roles of unique muscle and blood metabolites that track fuel metabolism. Altogether, these studies contribute to the scientific evidence base for recommendations related to exercise in pregnancy and childhood. "Dietary Influences on Psychological and Neuropsychological Development and Function in Children" Project: Data acquisition was completed for the longitudinal Beginnings study (described above) that examines relationships between early infant diets and cognitive development from infancy through 6 yr. This year, 50 participants were assessed, bringing to 389 the number of subjects completing the protocol. Resting brain electroencephalogram (EEG) recordings are documenting, for the first time, development of EEG "gamma" activity from infancy through 5 yr. EEG activity is critical for maintaining a balance between excitatory and inhibitory processes essential for normal brain development, learning and cognitive function. Specific gamma variations are being documented during the first 6 mos, a critical period of gamma development (518 infants, 1705 visits), and from 9 mos to 5 yr (466 infants and children, 2139 visits). Longer-term impacts of infant diet on preadolescent brain function will be tested in follow-up studies of the Beginnings cohort. Other studies are asking if infant diet or conditions associated with obesity are related to differences in childrens' brain structure and neural network activities. Non-invasive brain imaging (MRI, fMRI) and EEG technologies are used to evaluate brain measures at rest and during information processing. Data acquisition for two studies were completed this year: one relating differences in infant diet to brain function in preadolescents, and the other characterizing psychological and neurocognitive characteristics in obese preadolescents. Another study examines how breakfast meals differing in composition influence executive functions in obese children.
1. A woman's own expectation of gestational weight gain is a strong predictor of actual gain. Identifying predictors of weight gain during pregnancy could help reduce the adverse maternal and child outcomes associated with excessive gestational weight gain. Investigators in Little Rock, Arkansas, investigated whether a pregnant woman's preconceived weight gain expectations predispose to actual gestational weight. When controlling for important covariates, women who reported expecting to gain excessively were significantly more likely to gain excessively (51%) than those who expected to gain within recommended guidelines (37%). These new findings can form the basis for more effective public health and counseling strategies to help expecting women maintain a healthy weight gain during pregnancy.
2. Naturally-occurring gut bacteria (microbiota) may link aerobic fitness to liver health. High fitness levels have many health benefits including lower risk of cardiovascular and metabolic disease, and long-term benefits of fitness and exercise apply to children and pregnant mothers. The mechanisms by which being fit provides metabolic benefits is a matter of intense research and debate. Researchers in Little Rock, Arkansas, in collaboration with investigators at the University of Missouri-Columbia, investigated how aerobic capacity (a broad measure of fitness) in a rat model impacts accumulation of fat in the liver, a tell-tale sign of metabolic disease. They showed that more fit rats showed better adaptation to short challenges of diets high in fat, including better liver health, and these differences were associated with distinct gut microbiota independent of diet. The studies confirm the complex influence of fitness on metabolic health, and point to gut bacteria as new players to be considered as part of the network that associates exercise with changes in physiology and health.
3. Developmental programming of liver DNA by mother's obesity and diet. Obese individuals are at greater risk of developing fatty liver disease, which impairs liver function, contributes to poor blood sugar control, and can promote cirrhosis. While lifestyle determinants are important, the prenatal environment influences susceptibility to obesity and could therefore impact related outcomes such as fatty liver and steatohepatitis. Researchers in Little Rock, Arkansas, utilized a mouse model to examine the influence of maternal obesity/high-fat diet in liver inflammation and fibrosis in offspring. By employing cutting-edge methodology to monitor DNA modifications (methylation) at millions of sites in the genome, the investigators found that in response to high fat diets, offspring of obese mice had greater liver inflammation and fibrosis markers that associated with changes in DNA methylation. These findings suggest that maternal obesity detrimentally alters the ability of their offspring's liver to cope with challenges such as high-fat, inflammation-promoting diets.
4. Exercise-induced markers of fat-burning can trigger nerves that connect muscle to the brain. Fitness and physical activity have many health-promoting effects, and these benefits apply across the lifespan and in pregnancy. The regulation of exercise-induced muscle fuel combustion (fat, sugar or protein) remains to be fully elaborated, and it is not known what specific signals link metabolism to a person's perception of exercise fatigue and intensity. Researchers in Little Rock, Arkansas, in collaboration with investigators at the University of Utah, University of California-Davis, and Case Western Reserve University, investigated how an acute bout of exercise in sedentary and trained women impacts blood levels of fat and amino acid markers. Patterns revealed that exercise—regardless of one's fitness level—leads to enhanced but naturally inefficient fat fuel combustion, increasing by-products called acylcarnitines in the blood. Some of these metabolites activated specialized muscle-associated neurons, highlighting for the first time that by-products of fat metabolism have a potential to trigger exercise-related signals to the brain.
5. Role for lipid mediators in fatty liver progression to steatohepatitis in pediatric liver disease. Childhood obesity is a risk factor for a fatty liver, and children diagnosed with a fatty liver are at a higher risk for developing liver disease in adulthood. Little is known of the molecular mechanisms associated with predisposition toward pediatric development of fatty liver, but deciphering these factors would aid in crafting effective dietary and other strategies to minimize risk and improve liver health. Using a novel "knockout" mouse model (loss of two genes: glutathione-S-transferase-4 and peroxisome proliferator activated receptor alpha) that mimics pediatric liver disease pathology in children, scientists in Little Rock, Arkansas, discovered that specific lipid (fat) peroxide mediators promote liver cell injury and inflammation pathways implicated in liver disease. This novel animal model will be useful for testing the efficacy of dietary soy and other foods in limiting liver injury and inflammation associated with hepatic fat accumulation, which should have relevance to obese pediatric populations at high risk for liver disease.
6. The protein myoglobin as a carrier of fuel and spark to support muscle energy. Aerobic fitness increases with regular physical activity, and this is associated with health benefits in children and adults. Aerobic exercise requires the actions of the muscle-specific protein myoglobin, which is related to red blood cell hemoglobin that carries the oxygen necessary to burn fuels, such as fat. Scientists in Little Rock, Arkansas, collaborated with investigators at the University of Arkansas-Fayetteville and the University of Maryland in experiments that revealed a new role for myoglobin to bind fat and fat by-products called acylcarnitines. This novel finding supports an emerging view that muscle health and exercise are linked to the abundance and activities of myoglobin, and studies are underway to understand how this interaction impacts the muscle's ability to burn fat. Since muscle myoglobin abundance is responsive to exercise training, the results support the view that one mechanism by which physical activity improves health is through myoglobin-associated improvements in fat oxidation.
7. Breastfeeding and formula feeding lead to distinct differences in naturally-occurring gut bacteria ("microbiota"). Breastfeeding is strongly recommended as the gold standard of postnatal feeding, since it has been shown to promote gut and immune system development and reduce risk for allergies. These positive effects may be due in part to the interaction between breast milk components and naturally-occurring bacteria residing throughout the entire gut. Using a piglet model, researchers in Little Rock, Arkansas, demonstrated that formula feeding resulted in significant differences in the gut microbiota in both small and large intestine. This contributes to the scientific evidence base relating to breastfeeding recommendations, and the information can lead to better strategies for making specific formulas that promote a more natural gut microbiome for newborns.
8. Sensitivity to native language speech develops earlier in breastfed infants. The postnatal period between 3 and 6 months is an important time in early language development, since brain sensitivity to native compared with non-native speech begins to emerge. While it is increasingly accepted that early infant diet influences brain development, it is not known how postnatal diet influences the processing of native language sounds. Scientists in Little Rock, Arkansas, measured brain responses to native language syllables in 4 and 5 month old infants who were fed breast milk or formula (milk- or soy-based), and found that brain response measures of syllable discrimination and syntactic-related information (i.e., detection of patterns in syllable presentation important for later understanding of grammatical sentences) were greater in breastfed than formula-fed infants. The results suggest breastfed and formula-fed infants differ in onset of this critical period in speech development, and that sensitivities to native language speech properties are being established earlier in breastfed infants. The information from this study adds to the scientific evidence base supporting breastfeeding recommendations.
9. Maternal obesity is associated with changes in neonatal offspring brain function. Recent studies have suggested that being obese during pregnancy is associated with lower neurodevelopmental and cognitive outcomes of offspring. It is suspected that brain development in the fetus is affected by the obesity and metabolic health status of the pregnant mother. Scientists in Little Rock, Arkansas, used advanced magnetic resonance imaging (MRI) techniques to evaluate brain functioning in the prefrontal network in newborns born to obese and non-obese mothers. The results showed that the resting state functional connectivity in the brain, a measure of how different brain regions communicate with each other, is different in the brain prefrontal regions for the two groups of infants. This is consistent with studies which have observed brain functioning differences and/or cognitive functions controlled by these regions in older obese children, and provide new evidence that there are direct relationships between maternal obesity and alterations in children's brain development.
10. Maternal obesity impairs fetal bone cell development. Maternal obesity impacts the risk of chronic diseases, presumably via mechanisms involving changes to DNA structure and function (epigenetic mechanisms). However, evidence on the impact of gestational events on regulation of embryonic bone cell fate is sparse. Scientists in Little Rock, Arkansas, investigated the effects of maternal obesity on osteoblast bone cell development, and found that obesity was associated with increased cell senescence (aging) signaling. These findings indicate that in utero programming of fetal pre-osteoblastic cells can occur in response to maternal obesity, and may negatively impact bone cell differentiation and bone function in offspring. The studies provide a premise to determine if interventions that thwart maternal obesity or improve metabolic health in pregnancy can normalize bone cell activities in their offspring.
11. Dietary factors during early life program long-term bone formation. Bone health and osteoporosis risk in adults may be influenced by diet, exercise and obesity status during childhood; thus, public health strategies to maintain bone health throughout the life cycle and to prevent degenerative bone disorders in later life are urgently needed. However, it remains to be determined how early in development these factors impact bone function and growth, and which dietary components can influence bone turnover and integrity. Scientists in Little Rock, Arkansas, have discovered in a rat model that dietary soy protein isolate (SPI) during early life has persistent effects to promote bone development later in life. These findings revealed that short-term SPI diet early in life in rats has modest but persistent programming effects on bone formation which may help prevent degenerative bone loss.
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