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Research Project: Effects of Diet and Physical Activity on Maternal/Child/Adolescent Health and Development

Location: Microbiome and Metabolism Research Unit

2021 Annual Report

The mission of Cooperator's Arkansas Children's Nutrition Center (ACNC) is to determine the effects of diet, physical activity and nutritional status in childhood and in mothers during the pre- and post-conception periods on growth, development and health by conducting research on: 1) central nervous system and cognitive development and function of infants and children; 2) roles of maternal and child body composition, metabolism and genes (including responses to food macronutrients, phytochemicals and microbe-derived factors) on infant and child growth, development and the long-term health consequences of these factors; and 3) impact of parental and child physical activity on these parameters, singly or in combination with diet, and the biological basis for exercise-associated behaviors and health outcomes. To accomplish this mission, the ACNC has the following objectives and as appropriate, others as mutually agreed upon: A. Determine how maternal/parental diet, exercise, and metabolic health associate with psychological/behavioral, neurologic and physiological function and development in children. B. Understand how postnatal diet, childhood physical activity, and nutrition associate with psychological/behavioral, neurologic and physiological function and development in children. C. Characterize the interaction between the microbiome, host health and nutrition to modify physiology and promote health and development (skeleton, gastrointestinal and hepatic tissues, immune system, cardiovascular, and muscle, e.g.).

To accomplish these objectives, a research plan encompassing the specific research described below is authorized. Research is to be accomplished over a multi-year period as resources are available and as readiness for research and management capabilities develops. The plan shall be divided into the following areas: A. Determine how dietary components, dietary patterns, and metabolic health influence psychological-behavioral outcomes, neurodevelopment, and physiological function in children. Children will be studied longitudinally and cross-sectionally to evaluate the effects of child/parental diet, metabolic health, and body composition on psychological-behavioral, neurologic and physiological function. B. Determine how physical activity and fitness influence psychological-behavioral outcomes, neurodevelopment, and physiological function in children. Children will be studied longitudinally and cross-sectionally to evaluate the effects of child/parental physical activity patterns, fitness, metabolic health, and body composition on psychological-behavioral, neurologic and physiological function. C. Characterize the impact of host-microbe interactions on health and development. Children will be studied longitudinally and cross-sectionally to evaluate the factors linking child/parental microbiome with metabolic health, body composition, physical activity outcomes, psychological/behavioral, neurologic and physiological functions. D. Center Development. Cooperator has the following general areas of research in the Arkansas Children’s Nutrition Center (ACNC), which address the mission area of parental/child health: Brain Development and Central Nervous System Function; Dietary Factors and Physical Activity Effects on Health, Development and Function of Organ Systems (skeleton, gastrointestinal and hepatic tissues, immune system, cardiovascular, and muscle, e.g.); and Obesity and its Effects on Cellular and Physiologic Function in mothers, infants and children.

Progress Report
Project 1, Developmental Programming Associated with Maternal Diet and Obesity, research continues on Sub-objective 1A, which examines the impact of maternal high fat diet (HFD) and associated maternal obesity on offspring energy homeostasis, adipose tissue development, and metabolism. We have completed indirect calorimetry measurements on offspring exposed to maternal HFD at weaning and at 20 weeks of age. We are currently generating offspring for cold exposure studies. Sub-objective 1B, we will examine the effect of maternal HFD on fetal bone development via the repressor Ezh2 and subsequent decreased SATB2 expression. Offspring of osteoblast-specific Ezh2 knockout dams are being generated. Research continues on Sub-objective 1C, which examines the effect of maternal HFD on offspring vascular dysfunction. Genome-wide transcriptomic studies and vascular contractility studies assessing function of perivascular adipose tissue, smooth muscle, and endothelial cell function have been performed. Research continues on Sub-objective 2A, which examines the effect of oocyte-specific toll-like receptor (TLR) inflammation mediates the programming effects of maternal HFD. IACUC approval was obtained and animals are currently being bred to generate flox control and oocyte-specific Myd88 conditional knockout mice. Research continues on Sub-objective 2B, which examines the effect of placental TLR signaling on mediating the programming effects of maternal HFD. Placental assessments of inflammation from flox control and placenta-specific Myd88 mice have been completed. Project 2, Postnatal Factors Impacting Healthy Development, research continues on Sub-objective 1B,investigating the role of postnatal feeding practices and how it impacts long-term systems development. This past year, we have enrolled 21 participants (14 years). In total, we have enrolled 104 participants and will complete preliminary analyses on 1) age of menarche for girls and 2) bone mass accretion in children fed soy-based infant formulas compared to children fed human milk or cow's milk based formula to be presented at the European Society of Medicine this summer. Research continues on Objective 2 to determine if early life supplementation with blueberry derived phenolic acids suppresses bone resorption activities of osteoclasts and limits osteoblast senescence through the GPR109A. The results of the first set of experiments were published and in silico studies of niacin binding to GPR109A are being investigated. Research continues on Sub-objective 3A and 3B that will determine whether breastfeeding results in stronger immune function relative to infant formula feeding, how this relates to the gut microbiota and how microbial metabolites affect immune cell responses. Results have been published demonstrating that gastrointestinal metabolites are impacted by the neonatal diet in infants and in human milk fed piglets. Results on the effects of human milk oligosaccharides on immune cell composition and transcriptome analysis will be presented at two FASEB conferences. In addition, method to identify tryptophan pathway metabolites via mass-spectrometry has been established. Research continues on Sub-objective 3C examining mechanisms explaining how changes in host metabolic health influence the composition and function of the gut microbiota. The pilot study has been completed and a manuscript has been submitted. The study investigating the progression of diabetes and its impact on gastrointestinal tract has been completed, data analyses are ongoing. The study investigating whether the normalization of blood glucose in diabetic rats can restore the physiological changes has begun. Project 3, Antenatal Factors Impacting Obesity and Metabolism in Children, research continues on Sub-objective 1A which will determine if greater maternal weight during gestation increases infant weight and risk of childhood obesity at age 5 and 8 yr. We have completed 39 research study visits this year and have completed enrollment of all 5 yr old participants (N=117). Research continues on Sub-objective 1B where we are determining the impact of maternal BMI on the ability of the umbilical cord stem cells to differentiate into adipose tissue. This year, we were able to complete the adipogenic differentiation experiment on all of the cord samples (n=69). We are in the process of measuring the mitochondrial bioenergetics, mRNA and protein markers of differentiation. Research continues on Sub-objective 2A, 2B and 2C which will determine whether maternal exercise during gestation decreases the child’s susceptibility to obesity by age 2 years, alters the composition of the gut microbiota and decreases placental pro-inflammatory signatures. This year, we have enrolled 17 participants and have conducted 135 research study visits on 71 participants. 106 stool samples from 67 participants and 10 placentas were obtained. Research continues on Sub-objective 2D which will examine whether a community-adapted exercise intervention during pregnancy will be feasible and will demonstrate fidelity. This year, we have completed coding qualitative data from 10 interviews and 3 focus groups to identify key barriers, a concept mapping process to prioritize 6 key adaptations, and packaging all intervention materials for virtual delivery. Research continues on Sub-objective 3A which will investigate the effect of exercise and a healthy diet on reproductive health. This past year, we have enrolled 10 participants after the reopening of a fertility clinic and the center. Enrollment is ongoing. For Project 4, Pediatric Physical Activity: Mechanisms Impacting Health and Development, research continues on Sub-objective 1A, 1B, and 1C to determine the impact of physical activity, physical fitness, and obesity on mitochondrial function, substrate usage, and protein requirement in children. 51 children were enrolled in 1A. Of these, 7 were further enrolled in 1B to test substrate usage at a set work intensity and at an individualized exercise intensity. For Sub-objective 1C, the run-in diet was designed and the clinic site for stable isotope preparations was set up. Recruitment is ongoing; however, it was delayed due to COVID19. Research continues on Sub-objective 2A to determine if maternal weight status affects offspring physical activity from early life to pre-adolescence. The planned analyses of associations between maternal weight status and the physical activity level in their children were completed and are now being expanded using novel algorithms. Recall and testing of 5-year-old children were completed. Research continues on Sub-objective 2B to determine feasibility of a physical activity intervention in pre-school age children born to obese mothers. The population-level needs assessment is near completion, which was critical to inform adaptations to serve Arkansas families. Interviews of a subset of parents are in progress. Findings have been used to refine the at-home activity options. Institutional and IRB approval for group sessions was obtained this summer and recruitment is ongoing. Research continues on Sub-objective 2C to determine if early-life physical activity will result in persistent effects on energy and substrate metabolism. 100 pups were phenotyped as weanlings and tissues collected to comprehensively assay mitochondrial function. Studies were initiated to determine the metabolic impact of early life exercise exposure. Research continues on Sub-objective 3 to determine the role of muscle myoglobin in lipid trafficking. Due to a key scientist’s departure, delays were experienced. Mice phenotyping studies were completed. Preliminary studies of the interaction of myoglobin with the mitochondrial membrane were performed. Computational studies were also performed. Project 5, Dietary Influences on Psychological and Neuropsychophysiological Development and Function in Children, research continues on Objective 1 which will determine the effects of early diet on neurocognitive development in healthy children and adolescents. Data sets were organized and updated so that processing could be accomplished across all ages. Heart rate information was also analyzed to understand developmental changes in heart rate and vagal tone. While the milestones initially focused on the idea of evaluating language development within each age group separately, it became apparent that an important gap in the literature lay in the lack of high-quality data in a large study cohort addressing the development of the brain responses to heard language components. Thus, we chose to analyze the full data set from 3-24 months to provide these important data. Research continues on Objective 2 that will evaluate the impact of maternal obesity on brain development and function of their children in childhood. Recruitment and data collection is on-going for this study with 78 participants enrolled, and data pre-processing has been accomplished for 50 out of 78 data sets. Research continues on Objective 3 to determine the effects of diet composition, meal pattern and exercise on brain function and behavioral dynamics in normal weight and obese children. Data analysis has been completed for the initial study. Data collection and processing were completed for children with obesity recruited to the acute dietary intervention study. Preparation for data collection for Sub-objective 3B is underway, with the IRB protocol and consent documents being reviewed and finalized for submission.

1. Neonatal diet alters small intestine and circulatory metabolic outcomes. Breastfed infants have decreased rates of infections including respiratory tract infections, and certain breastmilk components impact the early life intestinal tract colonization (gut bacteria) in infants. Little is known about how these effects are related to each other. As an initial step to learn more about how human milk or dairy based infant formula affect intestinal, blood and urinary metabolites (small molecules), ARS scientists in Little Rock, Arkansas, have evaluated the abundance of metabolites in piglets fed with either human milk or dairy based infant formula until day 21 of life and weaned to a solid diet until day 51. The piglet model is intended to mimic the neonatal feeding in human infants. The ARS investigators in Little Rock, Arkansas, observed a clear separation in the metabolome between groups on day 21, but not on day 51. The current study demonstrates differential metabolic responses to human milk or dairy based infant formula not only during the exclusively infant feeding period but also after the transition to solid food.

2. Neonatal diet affects large intestine metabolome profile. While human milk is the preferred source of infant nutrition, most infants are fed infant formula during the first year of life. To better understand the differences between human milk and dairy based infant formula in modulating molecules present in the gastrointestinal tract,scientists in Little Rock, Arkansas, evaluated the abundance of metabolites (small molecules) in the cecum, proximal colon, distal colon, and in the rectum contents of piglets fed with either human milk or dairy based infant formula during the first 21 days of life and solid diet from day 21 until day 51. Infant formula improved cholesterol level and the bile acid synthesis as well as its excretion at age 21 days. Human milk enhanced utilization of fatty acids, polyamines and impacted the immune system. Our results demonstrated differential metabolic responses on energy utilization between human milk and infant formula feeding during the first 21 days of life, which was not sustained at age 51 days. Together, these findings provide new insights regarding nutritional responses at the distal gastrointestinal tract, which can be used to strategically enhance infant nutrition based on the metabolic response.

3. Formula diet influences urinary metabolite profile of infants at 3 months of age. Breastfeeding has been shown to provide better immune protection compared to infant formula, yet the mechanisms by which this happens is unknown. Scientists in Little Rock, Arkansas, analyzed the content of urine, which is less invasive than collecting blood samples and offers higher volumes for multiple downstream analyses, to identify the differences in metabolite profile in healthy 3 month old infants fed human milk, dairy milk-based, or soy protein-based infant formula. The main differences were seen between human milk and infant formulas. A dietary-specific pattern of urinary molecules produced from amino acids and monosaccharides were found in infants aged 3 months fed human milk, which might be linked to the microbial catabolism (breakdown) of proteins and carbohydrates. The soy protein-based infant formula enhanced the excretion of metabolites from polyphenols microbial catabolism. Overall, our findings indicate that urinary metabolites may mirror the infant's metabolism as noninvasive biomarkers and a potential tool to evaluate the impact of infant diets in early life.

4. Soy protein- and dairy-based infant formulas supports adequate growth and neurodevelopment up to age 6 years. The first 1,000 days of life have been identified as a critical window for growth and development. To learn more about how soy protein-based infant formula and dairy-based infant formula impact growth, body composition and neurodevelopment compared to breastfeeding, scientists in Little Rock, Arkansas, evaluated healthy term infants followed from 3 months to 6 years of age on these parameters. Body Mass Index was significantly lower between 2 and 6 years in breastfed children compared to children fed soy protein-based infant formulas during the first year of life. At 3 and 6 months of age, breastfed infants had significantly higher body fat than infants fed soy protein-based infant formulas, whereas breastfed children had significantly lower body fat at 3 and 4 years of age compared to children fed soy protein-based formulas. There were no differences in neurodevelopment at age 6 years between all children. These results demonstrate that human milk, soy-protein and dairy-based infant formulas support adequate growth and development in children up to age 6 years.

5. Blueberry derived phenolic acids impact bone development via GPR109A receptor. Blueberry contains small molecules called phenolic acids that may impact skeletal development and health. To better understand these effects, scientists in Little Rock, Arkansas, have investigated the role of the G protein-coupled receptor 109A (GPR109A) in metabolic bone homeostasis and osteoclast differentiation which has been identified as a mechanism by which blueberry treatment may affect skeletal health. Using densitometry bone histologic studies and molecular signaling analytic methods, researchers in Little Rock, Arkansas,uncovered that bone mass and strength were significantly higher in tibia and spine of rodents fed a standard diet at age 4-week and 6-month in mice with specific GPR109A gene deletion compared to their wild type controls. Blueberry derived phenolic metabolites significantly inhibited bone loss and increased bone formation in wild type mice but had no additional effects on mice gene deletion. These results suggest an important role for GPR109A during osteoclast differentiation and bone resorption.

6. Early life physical activity can affect bone health later in life. To learn more about the effect of early life physical activity on later in life bone health, scientists in Little Rock, Arkansas, gave mice access to a voluntary running wheel for 4 weeks and thereafter fed them either a normal fat or high fat diet for 8 weeks. Following the 8-week challenge, mice were provided a normal fat diet for 4 weeks. Early life physical activity increased bone mass later in life in mice that ate a normal fat diet. Eating a high fat diet caused later in life bone loss and early life physical activity did not prevent this high fat diet-induced bone loss and instead was associated with poorer measures of bone quality. This study highlights the complex interactions between the timing of dietary challenges and physical activity on bone development and bone health later in life.

7. Maternal overweight and obesity impact human milk oligosaccharides which influence infant growth. Excess maternal weight has been negatively correlated to breastfeeding. To better understand how excessive maternal weight changes human milk composition, scientists in Little Rock, Arkansas, investigated the difference in specific sugars (oligosaccharides) content of human milk from mothers with normal weight compared to mothers with overweight or obesity. Not only was the human milk from mothers with overweight and obesity different in oligosaccharides content, but also, infant intakes of these specific sugars was associated with greater growth and higher body fat content.

8. Infant home environment is associated with movement behaviors. To learn more about how the home environment regulates infants' physical activity, sleep and screen time, which are critical for optimal growth and development, scientists in Little Rock, Arkansas, explored these relationships in a healthy cohort of mother/child groups from age 6 months to 2 years. All families met the physical activity guidelines (more than 180 minutes/d), 72% of the families met the sleep guidelines (11-14 hours/d), and 45% of families met the screen time guideline (less than 1 hr/d). Children who met the screen time guideline and who met all three guidelines lived in homes with more developmental stimulation, organization, and toys. These results suggest that promoting routines (organization) and toys in infancy may help facilitate non-screen-based habits and healthy development.

9. Maternal obesity is associated with changes in human milk metabolome. Human milk is the main source of nutrition for breastfed infants during the first 6 months of life. Yet, there is little understanding of the impact of excessive maternal weight on human milk metabolites. To further our understanding, scientists in Little Rock, Arkansas, explored human milk composition using metabolomics analyses. Monosaccharides and sugar alcohols were increased in milk from women with overweight or obesity compared to milk from women with normal weight. Mannose, lyxitol, and shikimic acid concentrations predicted higher infant adiposity over the first 6 months of life. These results suggest that maternal obesity is associated with increased amounts of milk non-glucose monosaccharides that are also linked to greater infant body fat over the first 6 months of life.

10. Replicating effective programs: Using implementation science to adapt an exercise intervention for pregnant women. Replicating and implementing clinical results into a non-clinical community environment is critical to disseminate evidence-based practices. To achieve this goal, scientists in Little Rock, Arkansas, have published a new model called the Replicating Effective Programs model which guides the adaptation and implementation of an exercise intervention in obese pregnant women in a community environment. The model illustrates the phases of the adaptation process and reports on key targets for evaluating success. Importantly, it illustrates an intentionally designed and robust process of adaptation that can inform other translational research projects.

11. Markers of branched-chain amino acid catabolism are not affected by exercise training in pregnant women with obesity. Little is known about how exercise training during pregnancy affects metabolism. To better understand these effects, scientists in Little Rock, Arkansas, have determined the effect of a moderate intensity exercise intervention during pregnancy on blood levels of branched-chain amino acids and markers of their breakdown. Healthy pregnant women with obesity participated in an exercise or a non-exercise control group. The researchers in Little Rock, Arkansas,found no negative effect of exercise on branched-chain amino acids metabolism and concluded that exercise does not disturb movement of these building blocks to the growing tissue during pregnancy.

12. Fitness strongly associates with blood pressure status in children. Pediatric high blood pressure tracks into adulthood causing damage to the heart and kidneys, and unfortunately, high blood pressure medicines fail to prevent kidney injury. There is a need for effective treatments to protect target organs. Scientists in Little Rock, Arkansas, measured the association of fitness with blood pressure, markers of cardiovascular disease risk, and kidney function in 7-10 yr old children. Higher fitness improved blood pressure and kidney function in all children, regardless of their weight status. In children with obesity, higher fitness decreased the probability of high blood pressure, improved sugar metabolism and liver function. Increasing aerobic fitness should be considered a therapeutic strategy to counter pediatric high blood pressure, cardiovascular disease risks, and to protect the kidneys.

13. Dietary protein requirements in children. The dietary protein needs of children were determined decades ago using methods that we know today to be systematically flawed. These flaws may result in an estimated protein need of 60% less than what moderately active children actually require for support of normal growth and development. To understand the dietary protein needed for normal growth among children of all physical activity levels, new research using stable isotope amino acid methods should be performed. Scientists in Little Rock, Arkansas, published an article which reviews the current methods available to investigate pediatric dietary protein requirements and discusses methods to determine dietary protein requirements in children. Currently, there are not enough published data to overturn the current estimates.

14. Digital intervention strategies for increasing physical activity among preschoolers. Researchers have been using digital intervention strategies (computer games, tablets/iPads etc.) to increase physical activity (PA) among preschoolers; yet it is unclear what method of delivery and what content is best to achieve the highest increase in PA. Scientists in Little Rock, Arkansas, identified publications about digitally supported intervention studies for promoting PA in preschool-age children. In total, 5 studies applied an established behavioral theory to the design of the intervention, but did not find any clear patterns of effectiveness when applying the theory. No studies reported on implementation results related to adoption, cost, penetration (integration of the practice throughout the population), or sustainability of the intervention. The interventions with a significant effect on PA used child-centered activities. Our review highlights the need for research with rigorous designs, monitoring of implementation outcomes, and testing of the direct contributions of digital components to advance understanding of the effectiveness of digital interventions for increasing child PA.

15. Metabolic physiology and skeletal muscle phenotypes in male and female myoglobin knockout mice. Myoglobin roles for energy and substrate metabolism have been largely understudied. Scientists in Little Rock, Arkansas, used myoglobin gene deletion to better understand myoglobin's role in metabolism. Mice with gene deletion were viable, fertile and without any obvious signs of functional limitations. Transcriptomic analyses on different tissue types revealed few consistent changes along with capillary indices were significantly increased in mice with myoglobin gene deletion. The results indicate that myoglobin loss does not have a major impact on whole-body glucose homeostasis, energy expenditure, respiratory exchange ratio or response to a cold challenge in mice. However, the greater adiposity in female mice with myoglobin gene deletion indicates a sex-specific effect of myoglobin on fat storage and feed efficiency.

16. The potential role of globins in brown adipose tissue. Myoglobin regulates O2 bioavailability in muscle and heart as partial pressure of oxygen drops with increased tissue workload. Myoglobin is reported to bind and release nitric oxide in vivo and may increase the effectiveness of small ligands. Interestingly, myoglobin is present in brown adipose tissue, but its function is unknown. Scientists in Little Rock, Arkansas, presented a novel conceptual model of the role of globins in brown adipose tissue using studies in mice with myoglobin gene deletion. The novel concept suggests that myoglobin can serve as a net nitric oxide modulator, particularly in brown adipose tissue.

17. Pre-adolescent obesity is associated with difficulty in focusing attention on relevant information. Childhood obesity is known to represent a personal and public health problem due to the increased risk of chronic diseases with increasing evidence pointing to impairments in cognitive function that affect processes necessary for academic and social success. Scientists in Little Rock, Arkansas, looked at the ability of pre-adolescent children to shift from an on-going action to a different action when external events make that the best choice (cognitive inhibition). Results showed that obese children, while scoring lower on standardized tests for executive function and academic skill, did not differ in their ability to perform the task. However, there were significant differences in the way in which their brains solved the task indicating the obese children were less efficient at attending to external signals that required a shift in their behavior. These subtle changes are significant because the ability to monitor the environment and disengage from sub-optimal behaviors is a critical component of daily living that affects decisions from time management to avoidance of highly risky behaviors or overeating. Further, these data indicate that interventions to prevent additional weight gain and/or to reduce current weight in obese children must include measures aimed at improving executive functioning.