Research Project: Impact of Maternal Influence and Early Dietary Factors on Child Growth, Development, and Metabolic Health

Location: Microbiome and Metabolism Research

2023 Annual Report

Objectives
The overall objective of this project is to gather evidence about important environmental factors that have long-term consequences on child development/health, and their health as children become adults. The following objectives will be sought via five independent research studies: 1: Evaluate the role of epigenomic and postnatal factors in maternal obesity-associated programming of offspring metabolic, skeletal and cardiovascular outcomes. (Proj 1) 2: Determine the role of maternal germ line (oocyte) and placental (trophoblast) innate immune response signaling in mediating developmental programming in offspring. (Proj 1) 3: Determine the role of postnatal nutrition and dietary factors on physiology and metabolism. (Proj 2) 4: Determine if there is a persistent effect of early life nutritional factors on bone and metabolic health. (Proj 2) 5: Define host-microbiome cross-talk and xenometabolism in humans and rodent models relevant to human health. (Proj 2) 6: Examine the effect of maternal obesity, exercise and diet on programming the offspring's metabolism and risk of obesity during the first 8 years of life. (Proj 3) 7: Investigate the role of exercise during gestation in mitigating maternal programming of offspring metabolism. (Proj 3) 8: Test the feasibility and efficacy of peri-conception exercise intervention on mitigating maternal obesity programming. (Proj 3) 9: Determine bioenergetics phenotypes that link exercise to metabolic health in normal weight (NW) and obese (OB) children. (Proj 4) 10: Examine the persistent effects of early-life exercise, and the impact on childhood and adolescent metabolic health. (Proj 4) 11: Examine molecular signals and mechanisms associated with exercise, fatigue and muscle. (Proj 4) 12: Use participants in the Beginnings cohort to determine the effects of early diet on neurocognitive development in healthy children and adolescents. (Proj 5) 13: Evaluate the impact of maternal obesity on brain development and function of offspring in early childhood. (Proj 5) 14: Determine the effects of diet composition, meal pattern, and exercise on brain function and behavioral dynamics important for learning and school performance in lean and obese children. (Proj 5) 15: Determine the role of prenatal factors on mother’s health. 16: Investigate the role of prenatal factors and postnatal factors on infants’ health.

Approach
Studies will focus on: 1) the risk of obesity and development of key physiological systems are subject to programming at conception and maternal obesity and high-fat diets during pregnancy increase the risk of offspring obesity, and co-morbidities such as cardiovascular disease and non-alcoholic fatty liver disease. We will address specific mechanisms (Ezh2-mediated gene repression) in developmental programming and the role of specific signaling pathways in the placenta and oocyte per se in long-term programming via mouse models. We will examine developmental programming of adipose tissue and energy balance, bone health and osteoblast differentiation, and peri-vascular fat and vasculature, to address programming of weight gain, skeletal health and cardiovascular function. 2) the roles of postnatal and early-life dietary factors and the gut microbiota on host health and development through clinical and animal models to investigate how dietary and microbiome factors impact childhood development, and identify and characterize molecular cross-talk between microbes and the host. 3) clinical studies to investigate how maternal obesity can influence offspring development and health outcomes. We will explore differences in umbilical cord mesenchymal stem cells from infants born to normal weight and obese mothers for adipogenesis potential, lipolysis and mitochondrial bioenergetics. We will identify exercise-specific alterations in maternal gut microbiota during pregnancy as well as the direct effects of exercise on placental inflammation and placental nutrient transfer and its implication for long-term developmental programming in the offspring. 4) determine the impact of early-life physical activity (PA) on muscle and metabolic health, determine modifying effects of PA on energy and substrate metabolism, and determine specific muscle metabolic systems that associate with fitness, PA, fatigue and exertion phenotypes. We will determine bioenergetics phenotypes that reflect PA and obesity status, through studies of mitochondrial function in circulating cells, use of carbohydrates and fat during exercise, and optimal protein needs; focus on metabolic impact of early life PA by establishing the relation between maternal obesity and the child’s PA level, determine feasibility of a PA intervention in at-risk young children, and detail the molecular and metabolic pathways affected by early life PA. 5) measuring gut microbiome associations with immune and metabolic functions, and identify specific microbe-derived metabolites that could play a role. We aim to identify and characterize mechanisms of action of dietary components and gut microbes, which will improve formula diets for the benefit of a child's growth, development and immune function; identify mechanisms by which the gut microbiota influence both short- and long-term health outcomes; enable design of evidence-based interventions to thwart immune, bone and metabolic diseases; and identify microbial and/or host molecular mechanisms that can be targeted by diet or other interventions to prevent metabolic diseases and improve function.

Progress Report
Project 1: The impact of maternal high fat diet (HFD) on energy homeostasis, adipose tissue development and metabolism were examined. Metabolic phenotyping of postnatal diet studies was completed and transcriptomic and epigenetic experiments in adipose-derived cells from offspring are underway. It was found that deletion of Ezh2 in macrophage was associated with decreased bone resorption. Research continues to focus on how maternal HFD programs offspring vascular cells and cardiovascular outcomes. Heat shock protein expression has been investigated and analysis of vascular inflammation markers using flow cytometry has begun. A manuscript is under review. Project 2: Research continues to investigate the impact of postnatal feeding practices and on long-term development. Cooperating researchers in Little Rock, Arkansas, have enrolled an additional 16 participants (14y old) who were part of the original Beginnings study. In total, 138 participants (69 girls and 69 boys) have been enrolled. Preliminary analyses indicate no significant differences between children fed human milk, soy-protein based infant formula or dairy based infant formulas on growth, body composition, serum markers, age of menarche and bone mass accretion. Results on bone mass accretion between age 3m and 6y were published. Cooperating researchers in Little Rock, Arkansas, continue research on finding that global GPR109A deletion ameliorates sex steroid deficiency-induced bone loss through suppression of bone resorption. Fruit-derived phenolic metabolites are involved in facilitating bone development and protecting bone from degeneration. Associated mechanisms are being explored. Hippuric acid has been identified to have similar properties to niacin, and through computer simulations, was discovered to bind to GPR109A potentially regulating lipid metabolism and bone degeneration. Research examined how changes in host metabolic health influence gut microbiome composition. Cooperating researchers in Little Rock, Arkansas, found that leptin treatment in rodents with genetic predisposition to diabetes did not change gut microbial communities despite improvements in glucose homeostasis. Final stages of data collection exploring glucose homeostasis and colonocyte hypoxia are underway. Gut microbiome composition changes during diabetes progression have been found in this model, however, mechanisms remain unclear. A new collaboration with scientists at Univeristy of California, Davis will explore how comparative substate utilization alter colonocyte hypoxia. Project 3: Research continues to explore how greater maternal weight during gestation increases infant weight and risk of childhood obesity at 5y and 8 y of age. Cooperating researchers in Little Rock, Arkansas, have completed 38 study visits including collection of flow-mediated dilatation data. Analyses have been completed on 5y children. Research continues to determine the impact of maternal BMI on umbilical cord stem cell differentiation into adipose tissue. All samples and data analyses were completed. Adipogenic genes/protein expression and triglycerides data are being associated with metadata including child fat mass, gestational weight gain and maternal fat mass. Research continues to explore how maternal exercise during gestation decreases susceptibility to obesity by age 2, alters composition of maternal gut microbiota and/or decreases placental pro-inflammatory signatures. 115 study visits were completed this year, 37 prenatal and 48 postnatal stool samples were acquired, and 6 placenta/umbilical cord samples collected. A total of 527 fecal samples have been extracted and sequenced for 16S rRNA. Testing feasibility of a community-adapted exercise intervention during pregnancy. Cooperating researcher in Little Rock, Arkansas, completed all pre-testing of virtual and in-person components, informing an IRB modification and launch of a full pilot. Three women have been enrolled in Little Rock. Partnerships were developed in Pine Bluff, Arkansas, to expand the reach of this study. A publication on the process of adapting Expecting with community partner input was completed. Research to investigate the effect of exercise and a healthy diet on reproductive health has been halted due to continued COVID-19 impacts. Recruitment for investigation of exercise and healthy diet impacts on reproductive health were hampered by availability of only one fertility clinic in Arkansas, and a decrease of in vitro fertilization patients. With guidance from National Program Leadership, this research will not be completed and resources have been reallocated. Project 4: A cooperating researchers in Little Rock, Arkansas, continues research to determine the impact of physical activity, physical fitness, and obesity on mitochondrial function, substrate usage, and protein requirement in children. This year, 56 children were enrolled for physical fitness study and 33 were further enrolled to test substrate usage at submaximal exercise intensities. A manuscript on platelet mitochondrial function in children was published. A feasibility study of experimental diet preparation/palatability and protocol flow was completed. Enrollment in the full protocol is now underway. Research continues to explore if maternal weight status before/early in pregnancy affects offspring physical activity behaviors. A manuscript was submitted demonstrating sex-specific associations between maternal adiposity measured early in pregnancy and 2-year-old offspring's physical activity level. Data analyses from 5y olds are ongoing and testing of 8y olds is in progress. Collaborators in Little Rock, Arkansas, continue research on Objective 2. Feasibility of a physical activity intervention in pre-school age children of obese mothers was determined. Analyses of data from a pre-test phases have been complete and materials finalized for a full pilot. Qualitative data suggested strong acceptance and feasibility among parents. Quantitative data indicate improvements in body composition for mom and child and in locomotor and object control for children. Data have been used to refine processes for tailored intervention “homework,” incorporating nutrition education, increased frequency of gross motor skills testing, and refined session flow. Exploring how early-life physical activity results in persistent effects on energy and substrate metabolism. Rat pups born to parents with low cardiorespiratory fitness were found to have greater adiposity and altered whole body energy balance at weaning. Proteomics and bioenergetics alterations were observed in pup liver and muscle tissue. It was discovered that this phenotype can partially be reversed by early life exercise. A manuscript is under review. Collaborators in Little Rock, Arkansas, are exploring the role of muscle myoglobin in lipid trafficking. Mouse phenotyping studies and cell-based studies are complete. Pyruvate was found to interact with deoxy-Mb whereas lactate has higher affinity toward oxy-Mb. Computational studies revealed distinct interaction sites for oxy- and deoxy-Mb with the outer mitochondrial membrane. Project 5: Research on Objective 1 continues where collaborators in Little Rock, Arkansas, are studiing the impact of diet on development of infant brain and language-specific perception. All data, and collection procedures have been enumerated in a central location and data management protocols are in place to continue analyses. Language task data have been processed for infants (3-48 m) and children (6 y). Resting-state brain network interaction data have been published for infants (2-6 m), with data pre-processing completed for all participants. Research in Objective 2 continues to evaluate the impact of maternal obesity on brain development and function of their children. Data collection on participants from established cohorts at the ACNC has been on-going. Data preprocessing has been completed and data analyses are underway. Research on Objective 3 continues to determine the effects of diet composition, meal pattern and exercise on brain function and behavioral dynamics in children. Data collection has been completed, all data preprocessing is complete, with a manuscript under revision. Data analyses will include mathematical skills and resting-state brain network interactions. Initiation of a combined diet/physical activity intervention was slowed due to required modest revision to the study design. Project piloting is complete, and study has been initiated with first participants enrolled. Project 6: Research continues to determine the role of maternal obesity on the immune system during pregnancy. Data collection has been completed, data analyses and manuscript preparation are in progress. Research continues to explore the role of infant microbiota on gut and immune system. Animal studies are ongoing, data are being collected and analyzed. Animal studies are ongoing to examine the role of maternal diet and microbiota during pregnancy on maternal and offspring health. Data collection is underway.

Accomplishments
1. Evidence-Based Quality Improvement (EBQI) is an effective process to engage community partners in adapting interventions for community-based delivery. To better understand how evidence-based quality improvement can be effective to engage community partners, cooperative researchers in Little Rock, Arkansas, have conducted a case comparison of funded studies using EBQI to engage partners in the process of adapting intervention and/or designing implementation strategies for community delivery. Results identified key steps in the EBQI process including: (1) forming a local team of partners and experts, (2) prioritizing implementation determinants based on existing literature/data, (3) selecting strategies and/or adaptations in the context of key determinants, (4) specifying selected strategies/adaptations, and (5) refining strategies/adaptations. The Community Expecting study served as the central example of this process.

2. Maternal physical activity and lipid levels are associated with infant size at age 2 weeks. To better understand the relationship between maternal factors during pregnancy and infant size, cooperative researchers in Little Rock, Arkansas, have investigated physical activity levels and circulating lipids during pregnancy and infant size at birth and at age 2 weeks. Results demonstrated that higher physical activity during pregnancy is associated with lower lipid levels throughout pregnancy. The study also identified that circulating lipids during pregnancy are associated with infant size and body composition at age 2 weeks for women with excessive weight. These results suggest that higher physical activity during pregnancy is beneficial.

3. Education and Experiences of Antenatal Breast Milk Expression: A Systematic Review. To better understand the current evidence on antenatal breast milk expression, cooperative researchers in Little Rock, Arkansas, have conducted a systematic review of the literature on the education and experiences of antenatal breast milk expression until March 21st 2021. Results demonstrated that the literature is limited regarding antenatal breast milk expression with most studies focused on women with diabetes. The study also identified that the limited evidence suggests that antenatal breast milk expression may be a helpful tool in improving breastfeeding confidence and breastfeeding outcomes. These results suggest that future research is needed to better understand the effect of antenatal breast milk expression on breastfeeding outcomes in diverse populations.

4. Mother physical activity during pregnancy is associated with newborn’s brain development. To better understand the effect of physical activity during pregnancy on offspring brain development, cooperative researchers in Little Rock, Arkansas, have analyzed objective physical activity data obtained at 6 time points during pregnancy and have conducted MRI on their infants’ brain at age 2 weeks. Results demonstrated that there are significant relationships between physical activity during the first and second trimester and the brain cortical development in newborns. The study also identified that higher physical activity level was associated with greater brain cortical thickness, presumably indicating better cortical development.

5. Mother excessive weight during pregnancy is associated with infants’ microbiome during the first year of life. To better understand the relationship between maternal excessive weight and the infant microbiome, cooperative researchers in Little Rock, Arkansas, have examined infant fecal microbiome, short-chain fatty acids, maternal human milk oligosaccharides in 94 mothers with excessive weight and in 76 mothers with normal weight. Results demonstrated that maternal excessive weight is associated with a relative depletion of butyrate producing microbes during early infancy. These results suggest that overall microbial richness may aid in predicting elevated adiposity in later infancy.

6. Resistance training as an intervention in pregnant women with gestational diabetes mellitus. To better understand the effectiveness of resistance training in regulating blood glucose (sugar) concentrations in women with gestational diabetes mellitus (diabetes first identified during pregnancy), collaborative researchers in Little Rock, Arkansas, performed a literature review to assess the impact of resistance training on indicators of glucose management in gestational diabetes mellitus. They concluded that resistance training is emerging as a promising tool for blood sugar regulation in gestational diabetes mellitus, but it is important to address knowledge gaps to better maintain the health of mothers and offspring in pregnancies complicated by gestational diabetes mellitus.

7. Circulating microRNAs in young children differ depending on weight status and insulin resistance. To better understand if small molecules called microRNA (miRNA) circulating in the blood, differ between children of varying weight status and sensitivity to the insulin hormone, cooperative researchers in Little Rock, Arkansas, studied blood samples from 63 children, 5-9 yrs of age. For data analyses, children were divided into groups with either normal weight (NW, 20 children) or with overweight/obesity (OW/OB, 43 children), calculated using their height and weight relative to reference values. The OW/OB group was further divided into insulin-sensitive or metabolically healthy obese (26 children) and insulin-resistant or metabolically unhealthy obese (17 children), based on their glucose (sugar) and insulin concentrations in blood. No differences were observed in fasting glucose levels in blood, but insulin concentrations were elevated in the OW/OB compared to the NW group. Of 188 measured miRNAs, 11 were differentially expressed between NW and OW/OB groups. Similarly, certain miRNAs were correlated with the degree of resistance toward insulin. The investigators found evidence of early childhood differences and these findings may help in guiding targeted prevention of obesity-related disturbances at an early stage.

8. Exercise fitness testing can aid in early detection of heart irregularities. To highlight the value of exercise fitness testing in analyses of cardiovascular (heart and blood vessels) health, cooperative researchers in Little Rock, Arkansas, published a case study about an adolescent male who showed irregular heart and lung responses during a fitness bike test. Cardiovascular disease is often perceived as a problem for the older population, whereas irregularities during earlier years may be difficult to detect. In their report, the investigators described an abnormal test response in an otherwise asymptomatic teenage male, suggestive of early signs of cardiac dysfunction. The participant revealed a family history of early-age heart disease and a blood test showed increased level of an inflammatory marker. Repeated fitness testing over time might be important in adolescents with a family history of (early-age) heart disease, and may help guide in prevention of cardiovascular issues.

9. The energy production in platelets is associated with cardiovascular disease risk factors in children. To better understand how mitochondria (the powerhouses of cells) function are related to cardiovascular disease risk factors, cooperative researchers in Little Rock, Arkansas, measured how traditional markers of cardiovascular health (blood pressure, blood lipids, blood glucose (sugar), and aerobic fitness) associated with the mitochondria function in specific blood cells (platelets) in children 7-10 yrs old. Children attended one study visit after an overnight fast. Blood was collected, body composition was measured with the help of sophisticated equipment (DXA), and fitness level was measured by a bike test to peak performance. The investigators found that the ability of mitochondria to breathe (use oxygen) varied with factors like high blood pressure, obesity, and elevated low-density cholesterol (bad cholesterol). The data indicated that platelet mitochondria of children with both high blood pressure and low fitness have decreased ability to use the fuel necessary to produce energy. On the other hand, mitochondria function in platelets improved with increasing fitness. Future studies should determine the role of platelet mitochondria function in the development of cardiovascular diseases.

10. Regulation of myoglobin and its oxygen binding capacity in muscle cells. Myoglobin (Mb) is a protein in muscle cells that can bind oxygen for later usage in the mitochondria (powerhouses of the cell). Further, lactate (LAC) and pyruvate (PYR) are important byproducts of glucose (sugar) breakdown inside the cells. Cooperative researchers in Little Rock, Arkansas, found that when Mb interacts with LAC and PYR molecules, interesting things happen; In acidic conditions (corresponding to what happens during exercise), LAC interacts with Mb and makes it quickly release oxygen, while PYR has a stronger attraction to Mb when it does not have oxygen. Also, when Mb has oxygen, it sticks to the outer membrane of the mitochondria, and this helps in releasing the oxygen and converting Mb to a state without oxygen. These studies show that Mb plays a role in interacting with LAC and PYR, and this interplay is important in optimizing the delivery of oxygen to mitochondria. Depending on the acidity level in the cell, LAC prefers to bind to oxygenated Mb (Mb with oxygen), while PYR has a stronger affinity for deoxygenated Mb (Mb without oxygen). This suggests that when cells with Mb experience acidic conditions (such as during intense exercise or low oxygen levels), LAC can bind to oxygenated Mb, and as such, help in the release of oxygen into the cell and to the mitochondria, where it is needed in energy production. These data are important for our understanding of how energy production is regulated in muscle cells during various conditions.

11. Housing temperature can markedly alter energy metabolism in rodents. Rats and mice are used extensively in biomedical research to model human disease. However, discoveries made in preclinical rodent studies can sometimes fail to be useful in humans. One reason for this may be the conditions in which rodents are housed in research facilities. For example, temperature and humidity in rodent research facilities typically reflect those that are comfortable to humans (around 22-26°C). These temperatures may represent cold stress for rodents. To study this, cooperative researchers in Little Rock, Arkansas, housed mice in cages capable of continually measuring energy expenditure throughout the day. Mice were housed initially at 24°C, the standard temperature in their research facility. After a few days, the investigators increased the room temperature to 30°C. They found that this 4°C increase in housing temperature markedly lowered the energy expenditure of mice (i.e., the amount of calories burned across the day). The findings indicate that housing temperature should be an important consideration for researchers using rodent models to study human disease.

12. Deletion of the gene Ezh2 in bone precursor cells led to increased bone forming cells. Bone health is maintained by two types of cells – osteoblasts and osteoclasts – that work together to form new bone cells and break down old or damaged bone tissue. To learn more about the role of the gene enhancer of zeste homolog 2 (Ezh2) in maintaining bone health, ARS researchers in Little Rock, Arkansas, genetically engineered mice lacking Ezh2 in precursor cells that break down old bone tissue. Surprisingly, genetic deletion of Ezh2 in bone degrading precursor cells led to more bone forming cells and changes in genes involved in silencing bone breakdown cells. This study showed that changing Ezh2 expression in precursor bone degrading cells may be a way to treat or prevent bone disorders later in life.

13. Maternal high fat diet alters histone modification of specific bone formation genes. Studies in humans and animals models demonstrate that maternal high fat diets are associated with reduced bone density and increased fractures in offspring. There are proteins called histones that wind around DNA and package it in the nucleus. There are other proteins that can bind to histones and either wind or unwind DNA so some genes can be turned on and off. To understand more about the histone modifications that regulate genes involved in bone formation, ARS researchers in Little Rock, Arkansas, fed female mice a high fat diet and then studied histone modifications in bone cells in their offspring. Maternal high fat diet changed histone modifications on genes important in bone formation.

14. Identification of unique gene signatures in fat cells with activation. There are at least two types of fat cells – white and brown. White fat cells mainly store energy at fat while brown fat cells burn fat to generate heat. A prevailing theory to reduce or prevent obesity is that if brown fat cells can be activated more or if white fat cells can be transformed to behave more like brown fat, this might lead to weight loss through increased metabolism. ARS researchers in Little Rock, Arkansas, gave mice a drug that activates brown fat and used RNA sequencing to determine which genes change with this treatment in several different fat stores in the body. They discovered that beige fat has a unique set of genes that are expressed compared to white and brown fat and that beige fat responds differently to activation, which is important for furthering our understanding of how different types of fat regulate whole body metabolism and body weight.

15. Maternal diet and housing temperature modulate offspring microbiome composition and function. The gut microbiome plays an important role in host energy homeostasis and changes in the gut microbiome have been associated with obesity. Increasing brown fat activity to increase thermogenesis has been proposed as an intervention to treat obesity. To investigate how maternal diet during pregnancy affects offspring brown fat thermogenic activity and offspring microbiome, ARS researchers in Little Rock, Arkansas, fed female mice a high fat diet and then their offspring were given a drug to activate brown fat and stimulate thermogenesis. Maternal high fat diet changed the offspring microbiome response to brown fat activation. Housing mice at cold temperatures also changed the microbiome though the classification of bacteria that changed was different from the mice with brown fat activation. These studies provide further evidence that maternal diet during pregnancy is important in determining offspring health later in life.

16. The impact of obesity on cognitive function in children. Studies were designed to determine those areas in which overweight or obesity make it harder for children to succeed academically. Ideally, children of any body type or weight should have an equal chance at being successful so that they can be confident of their ability. Collaborating researchers in Little Rock, Arkansas, as have studies by others, that weight does impact a child’s ability to pay attention and to perform tasks that are important for success both in school and in the ‘real world’ like simple math. These differences are not always in the ability to complete a task, or get the answers to a problem correct, but are seen in the way the brain is actually working. These findings are significant because the changes we see in brain suggest that these children are at risk for loss of these abilities in adulthood or old age, particularly in cases where environmental adversity in high.

17. The impact of early infant diet on brain function. While breast feeding is considered the best choice for babies, it is not possible for all mothers and several options are available under those circumstances. Collaborating researchers in Little Rock, Arkansas, have looked at a large group of healthy infants (from 2 -48 months) to ask whether the brain is different in babies who were breast or formula (cow’s milk or soy milk) fed. We found that there are differences between feeding groups, but that those differences are only important at ages when a lot of changes in the composition of the brain is changing as it grows. In addition, we found that biological sex has a greater impact on differences in brain development than does diet. These studies are important because they suggest that a high-quality alternative to breast feeding does not adversely impact brain growth in early infancy.

18. Plant-based infant formula supports similar gut microbiota, metabolic and immune outcomes compared to a dairy-based infant formula. Breastfeeding is the gold-standard source of nutrients to infants with proven health benefits during early stages of development. However, due to several factors, infants receive formula diets in their early life when they are not exclusively breastfed. In fact, majority of the infants in North America received infant formula diets by 2 months of age. Although, dairy-based milk formulas are the most used alternatives to human milk, plant-based formulas can be a healthy alternative to infants and might be a dietary source to avoid cow-milk and soy-protein allergic reactions. An ARS researcher in Little Rock, Arkansas, leveraged animal model and demonstrated that a plant-based formula with buckwheat and almonds as the primary source of protein can support similar gut microbiota, metabolic and immune outcomes compared to a dairy-based infant formula.

19. Nutritional supplementation during pregnancy minimized heat-associated effects on birth outcomes of the child. There is emerging evidence that rising outdoor temperatures can be harmful to both mother and infant health. We also know that poor dietary intake (decreased intake of macronutrient and micronutrients) of the mother in addition to heat stress can lead to reduced growth of the baby. In this study, an ARS researchers in Little Rock, Arkansas, and collaborators from University of Colorado School of Medicine leverage a large multisite randomized trial, called Women First and found that women exposed to an excessive outdoor temperatures during the first trimester of their pregnancy were associated with babies that were shorter in length and head size at birth, and these effects were reduced when women received micronutrient supplementation before and during pregnancy. The mothers exposed to excessive temperatures also showed alterations to placenta gene expression and metabolites. These findings show that improving the diet of the mother through micronutrient supplementation may provide protective effects to the baby against rising outdoor temperatures.

20. Estrogen Receptor alpha (Era) is not essential in female protection against fat accumulation or changes in mitochondria function in the liver with high fat diet. Compared to males, premenopausal women and female rodents are protected against increased fat accumulation in the liver and improved mitochondria. Recent evidence suggest that estrogen, which is produced at greater levels in females, may lead to this protective effect, although it is unclear how. ERa is a nuclear receptor that is largely involved in signaling in estrogen signaling to change metabolic effects. In this study, an ARS researcher in Little Rock, Arkansas, and research collaborators from University of Kansas Medical Center found no differences in body weight/body fat or liver health in female mice with loss of ERa in the liver when given a high fat diet for either short-term (4 wk) or chronic (8 wk) duration. They also showed that loss of ERa in the liver prior to puberty or at puberty did not alter liver mitochondrial function but did lead to changes in liver gene expression and modest differences in bile acids.

Review Publications
Kracht, C.L., Redman, L.M., Bellando, J., Krukowski, R.A., Andres, A. 2023. Association between maternal and infant screen-time with child growth and development: A longitudinal study. Pediatric Obesity. https://doi.org/10.1111/ijpo.13033.
Diaz, E.C., Adams, S.H., Weber, J.L., Cotter, M., Borsheim, E. 2023. Elevated LDL-C, high blood pressure, and low peak V O2 associate with platelet mitochondria function in children -the Arkansas Active Kids study. Frontiers in Molecular Biosciences. 10:1136975. https://doi.org/10.3389/fmolb.2023.1136975.
Santos, D., Porter-Gill, P., Goode, G., Delhey, L., Sørensen, A., Rose, S., Børsheim, E., Dalgaard, L.T., Carvalho, E. 2022. Circulating microRNA differ in the early stages of insulin resistance in prepubertal children with obesity. Life Sciences. https://doi.org/10.1016/j.lfs.2022.121246.
Kasperek, M., Piccolo, B., Moody, B., Lan, R., Mailing, L., Gao, X., Hernandez-Saavedra, D., Woods, J., Adams, S., Allen, J. 2023. Exercise training modifies xenometabolites in gut and circulation of lean and obese adults. Physiological Reports. 11(6):e15638. https://doi.org/10.14814/phy2.15638.
Paz, H., Pilkington, A., Loy, H., Zhong, Y., Shankar, K., Wankade, U. 2023. Beta-adrenergic agonist induces unique transcriptomic signature in inguinal white adipose tissue. Physiological Reports. 11(6):e15646. https://doi.org/10.14814/phy2.15646.
Allman, B.R., Mcdonald, S., May, L., Borsheim, E. 2022. Resistance training as a countermeasure in women with gestational diabetes mellitus: A review of current literature and future directions. Journal of Sports Medicine. 52:2871–2888. https://doi.org/10.1007/s40279-022-01724-w.
Bhandari, D., Kachhap, S., Madhukar, G., Adepu, K., Anishkin, A., Chen, J., Chintapalli, S.V. 2022. Exploring GPR109A receptor interaction with hippuric acid using MD simulations and CD spectroscopy. International Journal of Molecular Sciences. 23(23):14778. https://doi.org/10.3390/ijms232314778.
Chen, J., Caviness, P.C., Zhoa, H., Belcher, B., Wankade, U.D., Shankar, K., Blackburn, M.L., Lazarenko, O.P. 2022. Maternal high-fat diet modifies epigenetic marks H3K27me3 and H3K27ac in bone to regulate offspring osteoblastogenesis in mice epigenetics. Epigenetics. https://doi.org/10.1080/15592294.2022.2111759.
Chen, J., Samuel, H., Shlisky, J., Sims, C., Lazarenko, O., Williams, D., Andres, A., Badger Thomas, M. 2023. A longitudinal observational study of skeletal development between ages 3 months and 6 Years in children fed human milk, milk formula or soy formula. The American Journal of Clinical Nutrition. 117(6):1211-1218. https://doi.org/10.1016/j.ajcnut.2023.04.002.
Debelo, H., Fiecke, C., Terekov, A., Reuhs, B., Hamaker, B.R., Ferruzzi, M.G. 2023. Compositional analysis of phytochemicals and polysaccharides from Senegalese food-to-food fortification ingredients: Adansonia digitata (baobab), Moringa oleifera (moringa) and Hibsicus sabdariffa (hibiscus). NFS Journal. https://doi.org/10.1016/j.nfs.2023.100144.
Edwards, T., Tas, E., Leclerc, K., Borsheim, E. 2023. Case report: A proposed role for cardiopulmonary exercise testing in detecting cardiac dysfunction in asymptomatic at-risk adolescents. Frontiers in Pediatrics. 11:1103094. https://doi.org/10.3389/fped.2023.1103094.
Gilbreath, D., Hagood, D., Downs, H., Alatorre-Cruz, G.C., Andres, A., Larson-Prior, L.J. 2023. Effects of early nutrition factors on baseline neurodevelopment during the first 6 months of life: An EEG study. Nutrients. 15(6):1535. https://doi.org/10.3390/nu15061535.
Na, X., Raja, R., Phelan, N.E., Tadros, M.R., Moore, A., Wu, Z., Wang, L., Li, G., Glasier, C.M., Ramakrishnaiah, R.R., Andres, A., Ou, X. 2022. Mother's physical activity during pregnancy and newborn's brain cortical development. Frontiers in Human Neuroscience. 10:943341. https://doi.org/10.3389/fnhum.2022.943341.
Paz, H.A., Pilkington, A., Zhong, Y., Chintapallisree, V., Sikes, J., Lan, R.S., Shankar, K., Wankhade, U.D. 2022. Gut microbiome and metabolome modulation by maternal high-fat diet and thermogenic challenge. International Journal of Molecular Sciences. 23(17):9658. https://doi.org/10.3390/ijms23179658.
Caviness, P.C., Dongzheng, G., Lazarenko, O.P., Blackburn, M.L., Fenghuang, Z., Jin-Ran, C. 2023. Decreased bone resorption in Ezh2 myeloid cell conditional knockout mouse model. Federation of American Societies for Experimental Biology Conference. 37(7):e23019. https://doi.org/10.1096/fj.202201673RR.
Sadler, D.G., Treas, L., Sikes, J.D., Porter, C. 2022. A modest change in housing temperature alters whole body energy expenditure and adipocyte thermogenic capacity in mice. American Journal of Physiology - Endocrinology and Metabolism. 323:E517-E528. https://doi.org/10.1152/ajpendo.00079.2022.
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Sobik, S., Sims, C.R., Crimmins, M., Bimali, M., Williams, D.K., Andres, A. 2022. Associations between maternal physical activity, maternal lipid levels, and infantanthropometric outcomes at two weeks of age.. Maternal and Child Health Journal. 27:18-177. https://DOI.org/10.1007/s10995-022-03558-4.
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