Location: Arkansas Children's Nutrition Center2019 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 activation 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 pre-partum to birth to infancy and childhood, provides critical information as to the long-term impact of early-life diet, maternal obesity, and factors such as exercise on the body's development (e.g., offspring's body fat and childhood obesity risk, bone health, gut and immune functions, brain function, muscle and cardiovascular health). In these projects, scientists in Little Rock, Arkansas, have discovered: new pathways that promote bone growth in response to fruit-derived phytonutrients; genetic mechanisms that promote obesity and abnormal bone growth in offspring from obese mothers; diet-, breastfeeding- and disease-responsive gut microbes that associate with immune function, obesity, brain anatomical and functional differences in children; liver cholesterol regulation in response to formula vs. cholesterol-rich breastmilk, comprehensive metabolite patterns from microbes and the host that correlate with metabolic health or exercise, and pathways in placenta and oocytes (mother's unfertilized eggs) that are pro-inflammatory in the obese state and link to early-life obesity-regulating events. Dietary Factors in Development: The Beginnings Study is the world's largest longitudinal study following growth, body composition, bone and brain development from birth-6 yr in children fed breastmilk, soy- or dairy milk-based formulas (n=300 ea.). Despite public controversy as to potential "phytoestrogen" effects of soy formula, no differences in reproductive organ development or general body growth were observed through 5 yr; a confirmatory study in Beginnings 14 yr olds is underway. In experiments examining if soy feeding activates estrogen receptor signaling and reproductive development in a pre-pubertal rat model, no adverse estrogenic effects were found. Thus, results to date indicate that soy has no effect on reproductive development. Phytoestrogens have also been implicated in promoting bone growth, and preliminary data indicate a modest improvement in bone in 5 yr olds fed soy as infants. The results from the project have provided key scientific evidence that is relevant to public health recommendations for, and production of, soy-based infant formula. This is important since not all mothers exclusively breastfeed and millions have chosen to feed their infants non-dairy, soy-based formulas. Effects of Early Diet on Gastrointestinal Development and Function: Breastfeeding is associated with an optimal immune system; yet, >50% of U.S. infants are formula-fed. How this impacts health and development remains to be established. We tested if dairy formula versus breastmilk-feeding impacts the natural ability to raise antibodies, utilizing a novel piglet model fed human breastmilk (HBM). Immune responses were greater following HBM feeding, and there were diet differences in the gut microbiota (the normal population of intestinal bacteria): signals from these microbes might confer beneficial effects on development of the immune response. The studies provide evidence for, and mechanisms associated with, a positive effect of breastfeeding on infant immunity. Formula vs. breastfeeding may also differentially regulate lifelong programming of cholesterol pathways: breastmilk contains ~4 times more cholesterol than dairy-based infant formulas, soy formulas contain no cholesterol, and many formulas contain vegetable oil with phytosterols (PS) that limit cholesterol digestion. Low dietary cholesterol causes the liver to adapt and produce more cholesterol: in piglet models (e.g., fed low or high PS and differing cholesterols in formula) liver cholesterol metabolism was ramped up with limited dietary cholesterol. Altogether, the project has contributed to the scientific evidence supporting breastfeeding as a public health goal, and has identified specific factors that can be modified in infant formula to optimize health and normal metabolism. The Role of Dietary Factors in Skeletal Development: Bone health and adult osteoporosis may be influenced by in utero conditions, diet, and obesity. The full suite of factors that influence bone turnover and integrity remain to be determined. Arkansas Children's Nutrition Center investigators discovered that maternal obesity drives abnormal offspring bone growth in rodents. These events are associated with DNA changes leading to altered offspring expression of specific factors (e.g., Ezh2, p300/CBP, SATB2) that promote bone cell senescence ("aging") or other outcomes linked to poor bone health. Many observations were replicated in human bone cells cultured from umbilical stem cells, illustrating that the systems can be regulated in humans. Separate studies identified the bone-promoting effects of specific fruit-derived nutrients (e.g., 3-(3-hydroxyphenyl)-propionic acid, rich in blueberries) and discovered the pathways likely involved in these processes. The results generated in this project have helped explain the mechanisms by which obesity and specific dietary patterns impact bone development. This new knowledge enables design of rational, science-based interventions and recommendations that promote optimal bone growth in children. Maternal Programming of Offspring Metabolism and Obesity & Interventions to Mitigate Maternal Obesity-Associated Programming: These studies have focused on intergenerational transmission of obesity and metabolic health from mother to child. Arkansas Children's Nutrition Center scientists identified key features of transmission: offspring fat utilization and storage, commitment and differentiation of stem cells, and placenta inflammation. This project has provided the groundwork for testing public health mitigation strategies including improving physical fitness in pregnancy. The Glowing Study is the first long-term study testing if maternal obesity influences offspring developmental programming of body fat from infancy to childhood (~300 mother-child dyads). It was discovered that maternal obesity and gestational weight gain associated with epigenetic changes to gene DNA in offspring, at least one of which (IGFBP1) is implicated in body growth. Analyses between mothers' obesity and metabolic health, and children's obesity and body fat outcomes, are being prepared for peer-review publication. Ongoing studies in 5 and 8 yr olds will provide a definitive test for the hypothesis that maternal adiposity programs offspring metabolism and obesity risk. In mice, maternal diet-induced obesity was found to program susceptibility of male offspring to obesity. Our research in mice and humans suggests the placenta is critical to obesity transmission: e.g., mice that lack placental MyD88 (important to inflammation) demonstrated that inflammation pathways are important for mother-offspring obesity transmission. These obesity-associated pathways are being evaluated in human placenta samples, and results indicate that they are involved in pre-pregnancy oocytes as well. The studies provide a first-ever glimpse into molecular underpinnings of mother-child obesity transmission. It was also found in mice that maternal obesity alters the composition of the offspring's gut microbiome. The microbiome may be a non-genetic pathway of transmitting obesity risk and could be targeted with specific early-life diets. The multi-year, longitudinal Expecting Study investigates if regular physical activity in obese pregnant mothers can ameliorate effects of maternal obesity-associated offspring programming of obesity, when compared to a pregnancy standard-of-care group (>160 women enrolled to date). The research has demonstrated that regular exercise significantly improves fitness level and metabolic health (e.g., blood sugar control) during pregnancy. The mechanisms that drive exercise- and fitness-associated health benefits and changes to the body's functions remain to be fully elaborated, but likely involve factors related to shifts in metabolism and muscle function. Research has established that muscle myoglobin (which gives muscle red color and ferries oxygen within the cells) binds fat molecules and likely plays an important role in regulating fat metabolism. Other studies identified novel molecules localized in exercising muscle that could have signaling roles relevant to fitness outcomes, fatigue and muscle health. Dietary Influences on Psychological and Neuropsychological Development and Function in Children: Studies have used non-invasive brain imaging (MRI) and brain EEG technologies at rest and during information processing, to test effects of maternal obesity programming, infant diet (breastfeeding vs. formula), and childhood feeding pattern (breakfast intake) on brain function. Data acquisition was completed for the Beginnings Study that has tracked the physical, physiological and behavioral development from up to 6 yr in children who were breastfed or fed milk-based or soy-based formulas. Resting cardiovascular and brain electrical activity measures from infancy through 6 yr will provide first-ever normative data describing sex and infant diet influences on autonomic and brain development. A second study identified a potential sex-related EEG-related biomarker associated with childhood obesity, and a related project was initiated that examines if a high-protein breakfast optimizes brain processes in obese preadolescents. A major outcome from this project (Beginnings study) is that through the 1st year of life, formula feeding alters brain electrophysiology outcomes compared to breastfeeding; however, these differences are small and formula-fed children remain well within normal with respect to neurocognitive and behavioral parameters. This is important since most children in the U.S. are not exclusively breastfed.
1. Soy infant formula feeding does not promote estrogen signaling pathways in the mammary gland. Soy infant formula contains isoflavones, molecules that potentially activate estrogen receptor pathways; this has raised a concern as to whether or not the use of soy formulas promote premature development in the estrogen-sensitive mammary gland. Investigators in Little Rock, Arkansas, used a neonatal piglet feeding model to investigate if soy formula feeding during infancy has any ill effects on development of reproductive organs during the postnatal feeding period. Soy formula feeding did not promote any estrogen-responsive signaling pathways associated with cell differentiation and ductal elongation, indicators of pre-pubertal development. Unexpectedly, both soy- and dairy milk-based formulas increased a measure of high cell growth in the mammary terminal end buds relative to a sow's milk control group, suggesting that formula feeding may initiate some tissue growth-associated pathways more than breastfeeding.
2. Maternal obesity impairs normal offspring bone development through mechanisms involving DNA modification. Programming of lifelong function of the body's systems is influenced by in utero and early-life environment, including mother's obesity or diabetes status; yet, the mechanisms by which inter-generational transmission of obesity-associated outcomes remain largely unknown. Scientists in Little Rock, Arkansas, have discovered that maternal obesity in mice leads to poor bone development in offspring. Using molecular biology techniques, it was discovered that a gene (SATB2) important to bone-forming cells (osteoblasts) was downregulated in offspring from obese mothers, and this appeared to be due to a factor called Ezh2 that was a site of DNA modification ("epigenetic" methylation) in response to obesity. Observations in a mouse model in which Ezh2 was removed confirmed better bone growth and higher SATB2 expression, and determinations made in human bone cells were consistent with the rodent studies. The results reveal, for the first time, specific molecular pathways that link poor bone health in offspring to obesity in mothers, and form a foundation to test if interventions such as improved diet, weight management or exercise can normalize these factors and hence improve bone development.
3. A mechanism by which dietary phenolic acid factors found in fruits such as blueberries can limit activity of bone-degrading cells. Bone health and osteoporosis risk in adults is influenced by diet, exercise and obesity status during childhood; thus, strategies to maintain bone health throughout the life cycle are urgently needed. Components of certain fruits such as blueberries have positive effects on bone growth, but specific pathways involved are not clear. Investigators in Little Rock, Arkansas, have characterized the effects of the blueberry- and plant-food molecule 3-(3-hydroxyphenyl)-propionic acid (3-3-PPA) and a related metabolite hippuric acid (HA) on activation of bone-degrading cells called osteoclasts. The investigators found that 3-3-PPA and HA reduce the expression of GPR109A, a receptor that was found to be a likely activator of bone-degrading cells. These findings support the idea that PPA-rich diets promote bone growth through increasing systemic phenolic acids, and indicate that fruits rich in these compounds can be complementary to other bone-promoting foods such as vitamin-D fortified dairy.
4. The metabolism of diet-responsive bacteria that normally are present in the intestines (gut microbiota) can impact kidney function. The collective activities of the billions of microbes residing in the gut are known to have a profound influence on almost all of the body's systems, but specific signals or pathways involved remain largely unknown. Scientists in Little Rock, Arkansas, in collaboration with investigators at multiple universities, have previously demonstrated that metabolism shifts accompany changes in the microbiome in response to dietary resistant starch. These associate with improved kidney function and reduced inflammation in a rat chronic kidney disease model. To better understand how dietary resistant starch impacts these systems, the team applied "metaproteomics" methodology that enabled a large-scale view of the 9000+ lower intestinal microbial and host proteins: some protein patterns suggested that the host's inflammatory status is ramped up with kidney disease and this could be dampened by dietary fiber, while other patterns support the idea that resistant starch reduces bacterial expression of proteins that break down the protective mucin barrier in the gut. These results illustrate that new technologies such as metaproteomics have great promise to fully evaluate how dietary factors alter health through changes in the abundances and activities of specific microbes in the gut.
5. Low cholesterol intake during infancy can alter normal liver metabolism. Breastmilk contains ~4 times more cholesterol than typical dairy-based infant formula, soy formulas contain virtually no cholesterol, and many formulas contain vegetable oil which has phytosterols (PS) that block efficient cholesterol digestion. Low dietary cholesterol in adults is known to trigger the liver to adapt and upregulate one's own pathways of cholesterol synthesis, but far less is known about how these systems are regulated during the neonatal period. Scientists in Little Rock, Arkansas, fed groups of 7 d old piglets different infant formulas containing high or low concentrations of PS and/or cholesterol for 3 wk, and found that higher cholesterol absorption was associated with a decrease in markers of liver cholesterol synthesis. These results suggest that typical infant low cholesterol/high PS formulas may induce or re-program liver cholesterol synthesis pathways in babies, and that reducing PS concentrations in infant formula may be a way to normalize dietary cholesterol metabolism in formula-fed children.
6. Blood metabolite profiling ("metabolomics") during exercise reflects changes in fuel metabolism and reveals that exertion acutely modifies levels of gut-derived molecules. It is well-established that weight loss and exercise improve metabolic health in muscle and other tissues, but the specific molecular factors that drive this healthy profile (or that signal exertion/fatigue) remain to be identified. To address this question, scientists in Little Rock, Arkansas, and their collaborators performed a comprehensive analysis of hundreds of blood metabolites during a moderate bout of exercise, both pre- and post- a ~14 wk training and weight loss intervention in obese, sedentary, insulin-resistant women. A novel observation was that exercise significantly increased several blood xenometabolites ("non-self" molecules, from microbes or foods); also, although exercise itself strongly impacted the blood metabolome, there were surprisingly few weight loss/fitness intervention-associated differences indicating that most exercise-responsive metabolic pathways in body are closely tethered to energy needs, regardless of weight loss or better blood glucose control. Finally, the study illustrates for the first time that exercise can modify circulating blood levels of factors derived from the gut bacteria, which may in turn influence how the bacteria signal to the host tissues during periods of physical exertion.
7. Obesity influences the follicular fluid surrounding unfertilized eggs (oocytes) in women of childbearing age. Maternal obesity has been shown to increase the risk of offspring obesity, but the mechanisms and timing of the events underlying this association remain to be established. It is possible that even before conception, the oocytes of obese women differ due to an altered milieu surrounding them, including the follicular fluid which provides a rich source of nutrients and factors requisite for oocyte growth, development and viability. Investigators in Little Rock, Arkansas, studied the impact of obesity on the follicular fluid content in normal weight and overweight/obese women undergoing fertility treatments. Using state-of-the-art methodology, it was discovered that there are obesity-associated changes in markers of oxidative stress, inflammation, antioxidant capacity, fatty acid oxidation, and lipid metabolism. Such findings suggest that obesity has important consequences on the follicular fluid content during the pre-conception period, a window of time that may be important for dietary or physical activity interventions to ameliorate offspring obesity risk and long-term child health.
8. Pre-pregnancy fat-free mass (FFM) is associated with sugar metabolism before and during pregnancy. A higher relative amount of fat-free mass (which includes muscles, bone and organs) is typically associated with better health outcomes and blood sugar (blood glucose) control, except in obese individuals where excess body fat appears to negate many of the positive impacts of FFM. These interactions are less well-understood during pregnancy, a time when a mother's metabolic health is thought to profoundly influence long-term programming of offspring metabolism and obesity risk. Investigators in Little Rock, Arkansas, have studied the association between FFM and body fat on glucose metabolism prior to and during pregnancy. The results suggest that the fat-free and fat weights have independent contributions to sugar metabolism during pregnancy, and it is hypothesized that muscle quality, rather than quantity, plays a key role in shaping maternal metabolic health.
9. Development of a new measure of metabolic health using blood cells from normal-weight and overweight/obese women. Mitochondria are often described as the powerhouses of the cells, using oxygen to convert food energy to the "energy currency" molecule ATP that drives tissue function. Skeletal muscle mitochondrial function is altered in metabolically unhealthy individuals (e.g., those with pre-diabetes or type 2 diabetes); however, obtaining a muscle sample is a complicated procedure, limiting the study of muscle mitochondria in vulnerable populations such as children and pregnant women. Scientists in Little Rock, Arkansas, tested if measurements of mitochondrial function and ATP-generating pathways in easily-obtained blood cells (platelets and peripheral blood mononuclear cells) could serve as a surrogate for measurements from small amounts of biopsied muscle. When patterns of mitochondrial respiration (oxygen consumption) in circulating PBMCs, platelets and muscle were compared, there were few significant correlations, indicating that global differences in mitochondrial function in blood cells do not reflect changes in muscle. However, secondary analysis indicated that mitochondria in circulating cells can themselves provide useful information about overall health status and, more specifically, differences in blood sugar control across the spectrum of normal weight to overweight/obese women.
10. Changes in the normal intestinal bacteria populations (gut microbiome) in response to fruit intake differ between females and males. Eating more fruits and vegetables is associated with reduced disease risk and optimal functions of the body's tissues, and part of this effect is thought to be through changes in the gut microbiome and related signals to the body. Investigators in Little Rock, Arkansas, used a mouse feeding model to ask, "How does fruit consumption impact the gut microbiome, and would this differ by sex?". A major finding was that the influence of a blueberry diet on shifting microbe species was clearly sexually dimorphic (different in females and males). This novel observation raises the possibility that male- and female-specific signals derived from the gut microbiota may modify the body's responses to fruit intake in a sex-specific manner; if true, this would support the idea that optimal dietary recommendations need a greater degree of personalization.
11. Brain structure and function during infancy, measured by magnetic resonance imaging (MRI), predicts behavioral and cognitive indices later in life. Researchers in Little Rock, Arkansas, and in other laboratories have demonstrated that early-life factors such as maternal obesity can alter offspring brain anatomy and function. Yet, the long-term ramification of these changes is not clear, and later-life measures of neurodevelopment and behavior are needed to correlate to early-life measures by MRI. Recruiting participants from the center's ongoing "Glowing" clinical study, the team collected MRI data from 44 babies and were able to recall 38 in order to quantify neurodevelopmental outcomes at 2 years of age by using the BSID-III toolset that measures: cognitive, language, and motor scales based on observation of the infants, and socioemotional and adaptive behavior scales (based on questionnaires completed by the parents). Even after statistically controlling for important covariates such as family's socioeconomic status, mother's age, body composition, breastfeeding duration, infant sex, demographic and home environment indices, it was discovered that infant global white matter brain development measured by MRI statistically associates with select BSID scores at 2 yr. This study illustrates the importance of understanding the underlying causes of early-life regulators of brain development associated with maternal obesity, in order to consider recommendations or interventions that can optimize brain health and function in offspring.
12. Early-life patterns of natural intestinal bacteria (gut microbiome) are sexually-dimorphic and influenced by maternal obesity. The microbiota in the gut are regulated by diet and other factors, and through mechanisms yet to be fully understood the microbiome can profoundly impact host health and function of many tissues. Studies conducted in Little Rock, Arkansas, leveraged a mouse model to determine developmental programming of the microbiome. It was found that maternal obesity led to distinct modifications in select gut microbes in both adult male and female offspring, highlighting a heretofore underappreciated phenomenon that can drive diet-independent differences in the offspring's microbiome. Certain maternal-influenced bacteria did coincide with obesity susceptibility in males only, offering some new targets to consider in the pursuit of factors that might explain, in part, the origins of sex-specific obesity susceptibility (males being more susceptible) due to early-life exposure to maternal obesity.
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