As the first federal nutrition research center to investigate the nutritional needs of pregnant and nursing women, and children from conception through adolescence, the Children's Nutrition Research Center conducts research that helps improve the maternal, infant and child nutrition guidelines used by physicians, parents and others responsible for the care and feeding of children.
Regulatory Aspects of Nutritional Metabolism
Despite advances in medical care, many infants in the U.S. are born prematurely, with low birth weight and increased risk of poor growth, development, and disease. Necrotizing enterocolitis (NEC), a leading cause of death in the preterm, has been linked to the feeding of infant formula compared to human milk and to poor gastrointestinal perfusion. Premature birth is also linked to lower lean mass and increased lifelong risk for metabolic diseases such as obesity and type 2 diabetes. The nutrients, arginine, citrulline, leucine, and choline play critical roles in tissue perfusion, nutrient availability, protein synthesis, immune function, fatty acid transport, neurodevelopment, and growth. The goal of this project is to identify the mechanisms that regulate the diminished growth and altered metabolic responses to nutrition in premature infants and to develop new nutritional strategies to optimize their growth and development and prevent disease. Our approach will be to use neonatal piglet models to fill these knowledge gaps. We will determine the extent to which the anabolic resistance to nutrition contributes to reduced muscle growth in the preterm and whether targeted amino acid supplementation will promote lean growth. We will determine the immune protective function of human milk and bovine colostrum-derived immunoglobulin A (IgA) and protection against NEC in the preterm. This project will ascertain the impact of citrulline and arginine supplementation on metabolism and prevention of NEC in the preterm. We will determine the optimum bioavailability of different chemical forms of choline that maximize the plasma and tissue deposition and function of long chain fatty acids in the preterm. This project is expected to provide novel information that will be directly useful in optimizing the nutritional management of premature and low birth weight infants and improve their long-term metabolic health and growth.
The ontogenic periods, when developmentally programmed control of gene expression is being established, are vulnerable to environmental influences, causing life-long functional consequences. Accumulating epidemiologic studies have demonstrated associations between early-life environment and an increased risk for common adult diseases such as obesity, cardiovascular (CV) diseases, and cancer. A major challenge, however, is to identify critical windows during which nutrition and other environmental stimuli have the strongest impact on disease risk. This project combines work of four independent investigators into a unified research theme to elucidate developmental origins of health and disease. We will use mouse models to study the direct contribution of maternal high-fat diet to the development of thermogenic adipocytes in offspring and identify the underlying transcriptional regulators. We will investigate how a gap junction protein Connexin43 affects the gene expression by epigenetic mechanisms and whether an early-life intervention on adipocytes can reprogram fat deposition, energy balance, and glucose and lipid metabolism in adulthood. We will utilize germ-free mice and gut microbiota transplant experiments to delineate epigenetic cross-talks between gut microbiome and intestinal stem cells at distinct developmental stages. We will also use mouse models to understand the relationship between diet in early life and the risk for developing cardiovascular dysfunction, and how these differ between sexes. Our multidisciplinary approaches will connect phenotypic effects with molecular, cellular, and physiologic mechanisms; apply state-of-the-science techniques for single-cell transcriptomics, genomics, and epigenomics; and use cutting-edge in vivo lineage tracing and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing tools to dissect the casual relationships. An integrated understanding of how diet, gut microbiome, and physical activity during critical periods of development lead to permanent changes in tissue structure, function, and epigenetic regulation throughout life should eventually lead to the design of early-life interventions to improve human health.
Regulatory Aspects of Obesity Development
With the prevalence of obesity and diabetes, non-alcoholic fatty liver diseases (NAFLD) are a major health challenge globally. Yet, the etiology of NAFLD remains unclear. We will investigate amino acid metabolism in the development and progression of western diet induced NAFLD. Epidemiological studies have shown correlations of aberrant amino acid profile with different stages of NAFLD. Yet, the role of amino acid metabolism in the onset and progression of fatty liver diseases remains largely unknown. Phenylalanine is an essential amino acid that has been found at high concentrations in the circulation of patients with steatohepatitis (NASH) and fibrosis. In contrast, branched-chain amino acids (valine, leucine, and isoleucine) are high in patients with NASH but low in patients with fibrosis. Our preliminary data show that phenylalanine is required for preadipocyte differentiation and lipogenesis, suggesting phenylalanine may contribute to lipid formation in the liver as well. Furthermore, dietary phenylalanine restriction protects mice from high-fat diet-induced obesity and this protection was reversed in part by elimination of the gut microbiome. In this proposal, we will test our hypothesis that nutritional availability of phenylalanine alters the gut microbiota to affect host metabolism and susceptibility to NAFLD. Together, the results will reveal the importance of amino acid metabolism, particularly phenylalanine metabolism, in NAFLD.
Principle Investigators: Gao
This project combines work of two independent scientists investigating molecular mechanisms in diet-related chronic disease. Cancer is one of the leading causes of illness and death worldwide. Overweight and obesity increase the risk of certain types of cancer, as does a diet high in processed foods and unhealthy fats. However, the molecular mechanisms driving these associations remain unclear. Variation in RNA processing, including alternative polyadenylation and alternative splicing, is influenced by nutrition, and associated with cancer risk. However, the role of nutrient-induced mRNA processing in cancer is uncharted. We aim to decode and investigate diet-induced RNA processing and the underlying molecular mechanisms to guide nutrition interventions for cancer prevention. Metabolic programming occurs when nutrition affects development, causing structural or functional changes that influence later health. Nutrition affects developmental epigenetics, particularly DNA methylation, making it a prime mechanism for metabolic programming. We pioneered the identification of human genomic regions of systemic interindividual epigenetic variation (CoRSIVs) to accelerate progress in this area. We will identify CoRSIVs in African Americans and determine if CoRSIV methylation in African American newborns predicts childhood obesity. We will also identify mouse metastable epialleles (a subclass of CoRSIVs) and test associations between methylation at these loci and later obesity. A better understanding of how nutrition affects these various molecular mechanisms should eventually lead to the development of nutritional interventions to improve human health.
Principle Investigators: Waterland, Yalamanchili
Abnormal eating habits can manifest as health-threatening and socially impactful chronic disorders, e.g. obesity. Obesity-associated health complications, such as diabetes, account for one of the leading causes of death in the United States, and obesity-related health costs pose a financial burden of nearly 150 billion dollars annually. Neural circuits in the brain coordinate proper energy and glucose homeostasis. Disruptions in these networks dramatically affect eating behaviors, resulting in nutritional imbalances with adverse impacts on human health. Thus, identification of key neurons, their circuits, and the intra-neuronal signaling mechanisms that regulate feeding behavior and glucose balance represents a needed step towards developing new and effective therapeutic strategies to treat obesity and diabetes. Dr. Arenkiel’s lab has demonstrated critical roles for cholinergic neurons to regulate feeding behavior. He will continue to unravel the neurocircuits utilizing cholinergic neurons for feeding regulation. The Fukuda group discovered that central administration of a small dose of the antidiabetic drug metformin can correct high blood glucose levels in mouse models of type 2 diabetes. Since AMPK is potently activated by metformin and is considered to mediate at least some of the effects of metformin, he will test the new hypothesis that AMPK in the brain responds to metformin as well as to distinct nutritional conditions to control whole-body glucose metabolism. Sisley (a physician-scientist) observed that some children with severe, early-onset obesity and dysregulated satiety had heterozygous loss of 2 different ciliary genes (digenic heterozygous), which involved the loss of ALMS1 with different BBS genes. She will test the hypothesis that digenic heterozygous loss of ciliary genes causes a fundamental defect in ciliary function and results in obesity.
Enhancing Childhood Health and Lifestyle Behaviors
Energy expenditure (EE) in children is influenced by their physical activity (PA), sedentary time, duration and quality of sleep, and circadian rhythms, which ultimately affect their adiposity and metabolic health. Screen media use is a significant contributor to sedentary time and is more strongly associated with greater body fatness and lower EE compared to other types of sedentary behaviors. However, the relationship between television (TV) viewing and adiposity is not well understood. In addition to screen use, sleep duration, timing, and circadian stability predict greater adiposity levels and weight gain in children. The mechanisms underlying the relationship between sleep, circadian stability, and body mass index are unclear, though the impact on daytime resting EE during screen use is a potential mechanism that has yet to be examined. Sleep dysfunction can also interfere with energy metabolism in children and emerging studies suggest that short sleep duration and sleep dysfunction negatively impact bone metabolism. However, the underlying mechanisms remain undefined. The interaction between sleep and adiposity on bone health is also not clear. Lastly, low levels of PA, excessive time in sedentary behaviors, and shorter sleep durations increase the risk of youth-onset type 2 diabetes (T2D). Children with T2D are at higher risk of chronic comorbid conditions including hypertension, dyslipidemia, and dysregulated amino acid metabolism. Rigorous studies of children’s PA, sedentary time, and/or sleep will be conducted in four different samples: 1) diverse healthy preschool aged children, 2) diverse adolescents with or without obesity, 3) Hispanic adolescents at risk for T2D, and 4) diverse adolescents with pre-diabetes to examine the mechanism(s) for which PA, sedentary time, and/or sleep influence children’s risk of obesity, bone and/or metabolic health to address five objectives. Findings will help inform intervention, prevention, and guidelines to promote better metabolic health among youth.
Principle Investigators: O’Connor, Bacha, Moreno, Soltero, Tosur
Currently, 22.4% of 2-to-19-year-olds in the US have obesity, an all-time high. Obesity increases throughout childhood and adolescence and tracks into adulthood. Once established, it is difficult to treat or reverse, strengthening the case for primary prevention. Consuming an unhealthy diet increases the risk of obesity, chronic diseases (e.g., cardiovascular disease, diabetes, several cancers) and earlier mortality. Estimates are that from 2021-2023, obesity, cardiovascular disease, diabetes, and diet-related cancers alone will cost the US $2.9 trillion in healthcare expenditures. Overweight and obesity are the most significant diet-related risk factors, making child and adolescent obesity prevention a key factor in reducing chronic disease risk. Understanding drivers of obesity among children from under-represented families who are at a greater risk for developing obesity is a public health priority. Likely drivers include a lack of understanding or adequately addressing influences on childhood obesity such as: a) the role of residential location; b) how parents approach feeding their child including the emotional climate created by those interactions (e.g., feeding styles); c) household fruit and vegetable (FV) purchases; and d) food and nutrition security. Three independent, but related, research projects, guided by the Socio-Ecological Model, will address these knowledge gaps. Our sub-objectives will produce content for a digital obesity prevention intervention tailored to teens in rural communities (1.A.); investigate the development of childhood obesity among families with low-incomes using qualitative strategies to gain a better understanding of family interactions around food (1.B); and explore FV purchases among low-income households with children, specifically using Supplemental Nutrition Assistance Program Electronic Benefit Transfer and its association with home FV availability, and food and nutrition security (1.C.,1.D.). These projects address important knowledge gaps, thereby establishing a firm foundation for future child obesity prevention interventions for under-represented youth, and guide policies affecting federal nutrition assistance programs.
The Dietary Guidelines for Americans (DGA) 2020-2025 highlighted the urgent need for studies into whether the intake of non-human non-formula milk foods and beverages influences children’s cognitive development prior to 24m of age. During early infancy (0-6 months [m]), children should receive all of their nutrition through human/formula milk. From 6- 12m children undergo a transition period, during which complimentary foods and beverages (CFBs) are introduced, but their nutritional needs are met through human/formula milk. While this period of 6-12m may have important implications for cognitive development, the current project aims to address the need for a greater understanding of the role dietary intake plays in supporting cognitive development from 12-24m of age, since this is the earliest time when most children’s major nutritional needs are met via non- human/non-formula milk sources. This research need will be addressed in two ways: due to the well- known difficulties of measuring dietary intake in young children, one aspect of the project will leverage existing observational data on over 8,000 US and European children, available from, The Environmental Determinants of Diabetes in the Young (TEDDY) study and examine associations between parent-reported dietary intake with metabolome-wide metabolites from ages 12-24m. The goal of these analyses is to identify generalizable biomarkers of dietary intake, useful for wide-ranging future studies into diet-health associations in toddlerhood, including those focusing on neurocognition. Due to the lack of existing data on dietary intake and cognitive development in toddlerhood, a second aspect of the project will establish a new longitudinal cohort of toddlers in Houston. Since we are interested in the effects of diet from 12m on cognitive development, and such effects may take time to accrue to the extent that they are observable in a research setting, children will participate in study visits at 18- and 24m of age. At these ages, the project aims to measure habitual dietary intake over the past six months, quantify metabolome-wide metabolites, and assess cognitive development in up to 150 children. This new cohort will represent the start of a unique, and needed, resource for the scientific community, given our lack of data on diet and cognitive development in toddlers. It will also provide information for epidemiological analyses within the project period, that examine associations between dietary intake from 12-24m of age, and of diet- related metabolites, with cognitive functioning at 18-24m. These related, but independent, project goals represent some of the first attempts to collect information on the associations of diet with cognitive development in toddlerhood – information which could help policymakers develop improved food and nutrition policies and programs. Furthermore, this information will impact multiple key stakeholders, such as the food industry, dietary professionals, health care professionals, and new parents.
Principle Investigators: Wood
Lactation and Nutritional Health
Lactation is a physiological state that requires a profound increase in energy demand to meet the nutritional requirements of the mother and the offspring. Despite the well-known benefits of lactation for both the mother and offspring, there is a paucity of metabolomic data in lactating dams. Metabolic adaptation in the dam is coordinated by central (brain) and peripheral (such as, liver) driven mechanisms that include changes in maternal feeding patterns (hyperphagia), redirection of energy mobilization to facilitate milk production, and cholesterol and glucose metabolism. The cellular mechanisms driving these processes are known to be regulated transcriptionally, and mutations in these genes contribute to a variety of metabolic disorders. To address these knowledge gaps, we will use genetically modified mouse models to determine the impact of central and peripherally regulated metabolism in dams at various stages of lactation. These studies will identify novel neuroendocrine mechanisms that impact maternal feeding behaviors and energy utilization, cholesterol metabolism and glucose homeostasis, and long-term metabolic adaptation that are essential for lactation. These findings will provide therapeutic and diagnostic targets that improve lactation outcomes and sex specific mechanisms for protection of mothers against metabolic diseases.
Principle Investigators: Wooten-Kee, Wang
Impact of Dietary Components of Health
We know that a diverse diet, which incorporates fruits and vegetables, contributes to a healthy diet for children, and pregnant and lactating females. However, the mechanisms by which specific components in these foods affect health are critical gaps in our knowledge. This project will focus on carotenoids found in human milk and the phytochemicals hypoglycin-A and sulforaphane. First, carotenoids are phytochemicals, which confer the golden color of early milk, known as colostrum, and are present in milk of all lactation stages. We will investigate the degree to which carotenoid intake and physiologic factors predict colostrum, transitional milk, and mature milk carotenoid composition in healthy lactating mothers. Second, we will test the effect of carotenoids on oxidative stress, inflammation, growth, and differentiation of in vitro muscle and adipose cells as a model of infant physiology. Last, increased gluconeogenesis (GNG) is a major contributor to fasting hyperglycemia, an early pathological feature of type 2 diabetes (T2D). We will investigate the nutritional significance of hypoglycin and sulforaphane, two compounds found naturally in certain fruits and vegetables, in the regulation of glucose metabolism. We will test the hypothesis that these compounds will improve glucose metabolism by increasing whole-body and hepatic insulin sensitivity, which in turn elicits increased glucose utilization plus reduced glucose production via suppression of gluconeogenesis in a mouse model of T2D. If proven true, these compounds potentially can be used as adjuvant therapy in conditions of chronic hyperglycemia such as obesity and poorly controlled T2D. The data from this study would support the health benefits from the increased consumptions of certain fruits and vegetables. Filling these gaps in knowledge will present future opportunities to develop rational, mechanism-backed dietary recommendations to support optimal health and nutrition.
The long-term goal is to contribute knowledge useful in the development of strategies aimed at securing a more nutritious food supply. In this study we will first address nutritional and productivity issues commonly associated with climate change by genetically modifying genes in the model legume, Medicago truncatula that have the potential to enhance drought tolerance or to improve nutritional quality by reducing the antinutrient, phytate. Plants exhibiting the desired modification(s), either singly or in combination, will be assessed for changes in nutritional quality and productivity under abiotic and non-stress conditions. Investigation into the mechanisms conferring the drought tolerance and nutritional improvement will be initiated using molecular-genetic methodologies. A second aspect of this project will focus on steroidal alkaloids and developing novel systems to intrinsically label crops. Steroidal alkaloids are bioactive molecules prominent in tomatoes, which account for ~25% of American vegetable consumption. Determining their bioavailability and metabolism is critical to understanding their role in health. Systems to efficiently generate intrinsically labeled crops will further our understanding of plant metabolism, phytochemical bioavailability, and better define human nutritional needs. Thirdly, experiments will be conducted to investigate the impact of calcium oxalate consumption from plant-based diets on the microbiome. This investigation is relevant to public health because microbiota-directed complementary foods are promising strategies to use diets to feed beneficial bacteria, which can help both children and adults thrive. However, how these plant foods work is still being determined; this study identifies how calcium oxalate consumption alters microbiome composition and impacts nutrient absorption and bone density. This fundamental knowledge will improve diets to enhance health and reduce illness. Overall, the information gained will provide scientists a better understanding of the factors regulating plant nutritional quality and productivity.
