Assessing Food Intake and Physical Activity of Children
Despite improvements in their nutritional management, most premature and low birth weight infants have experienced growth faltering by discharge. Many remain small to adulthood and are at an increased risk for developing metabolic diseases such as obesity and type 2 diabetes. The goal of this project is to identify the mechanisms that regulate the diminished growth and altered metabolic responses to nutrition in premature and low birth weight infants and to develop new nutritional strategies to optimize their growth and development. Our approach will be to use neonatal piglet and rodent models to fill these knowledge gaps. We will determine whether being born prematurely blunts the anabolic response to feeding and identify mechanisms by which amino acids, particularly leucine, regulate lean growth. We will determine the role of the enterokine, FGF19, in the anabolic response to enteral feeding in the preterm and whether augmentation of its secretion will enhance growth and metabolic function. We will establish the mechanisms by which undernutrition during critical windows of postnatal development impacts proliferation of skeletal muscle stem cells and the mature muscle nuclear number. Further we will test whether methyl group deficiency induced by inadequate amino acid supply results in permanent epigenetic modifications that impact muscle growth. This project is expected to have a positive impact by providing novel information that will be directly useful in optimizing the nutritional management of premature and low birth weight infants and improving their long-term metabolic health and growth.
Research Faculty: Douglas Burrin / Teresa Davis / Marta Fiorotto
Regulation of Glucose and Gluconeogenesis and their Roles in Type-2 Diabetes and Obesity
One of the most significant abnormalities underlying type 2 diabetes is continued production of glucose by the liver (gluconeogenesis). Thus, understanding the mechanisms by which gluconeogenesis is regulated is paramount to effectively treating type 2 diabetes. In this project, independent researchers are investigating three mechanisms that are likely involved in glucose regulation by the liver. Objective 1 will determine if vitamin D receptors in a specific area of the brain, the ventromedial hypothalamus (VMH), are important for glucose control. Objective 2, containing three components, will determine the role of leptin and the leptin receptor in hepatic gluconeogenesis and investigate the nutritional significance of certain small molecules in reducing glucose production via gluconeogeneic pathway. Objective 3, with two subobjectives, will determine the mechanisms of SIRT3, a mitochondrial protein, to regulate gluconeogenesis. Together, these projects will advance our understanding of how the liver regulates glucose production using neural, hormonal, and intracellular mechanisms, and increase the overall body of knowledge.
Research Faculty: Stephanie Sisley / Shaji Chacko / Qiang Tong
Epigenetic Mechanisms Mediating Developmental Programming of Obesity
Developmental programming occurs when nutrition and other environmental exposures affect prenatal or early postnatal development, causing structural or functional changes that persist to influence health throughout life. This project combines work of two independent investigators working to understand epigenetic mechanisms of developmental programming. Epigenetic mechanisms regulate cell-type specific gene expression, are established during development, and persist for life. Importantly, nutrition during prenatal and early postnatal development can induce epigenetic changes that persist to adulthood. We focus on DNA methylation because this is the most stable epigenetic mechanism. The inherent cell-type specificity of epigenetic regulation motivates development of techniques to isolate and study specific cell types of relevance to obesity and digestive diseases. For this reason, these projects integrate both detailed studies of animal models and characterization of epigenetic mechanisms in humans. We will use mouse models of developmental epigenetics in the hypothalamus to understand cell type-specific epigenetic mechanisms mediating developmental programming of body weight regulation. Mouse models will also be used to investigate how folic acid intake affects epigenetic mechanisms regulating intestinal epithelial stem cell (IESC) development and characterize the involvement of these mechanisms in metabolic programming related to obesity, inflammation, and gastrointestinal cancer. In human studies, we will identify human genomic loci at which interindividual variation in DNA methylation is both sensitive to maternal nutrition in early pregnancy and associated with risk of later weight gain. An improved understanding of how nutrition affects developmental epigenetics should eventually lead to the creation of early-life nutritional interventions to improve human health.
Research Faculty: Rob Waterland / Lanlan Shen
Body Weight and Health Consequences
The long-term objective of this project is to provide an enhanced understanding of how altered bone metabolism in the childhood years contributes to long-term skeletal health and may play a role in glucose metabolism and cardiovascular health in obese children by examining the evolution of risk factors and biomarkers of bone health early in the course of obesity and type 2 diabetes (T2DM). Specifically, we will investigate the effect of adiposity, adipokine dysregulation, insulin resistance and vitamin D concentrations on bone microarchitecture, bone biomarkers and vascular health in youth with and without abnormalities in glucose metabolism. Given the importance of vitamin D to bone mineralization and a host of metabolic functions, we will also examine whether restoration of vitamin D sufficiency, in a randomized placebo controlled study design, has a positive effect on bone microarchitecture, bone biomarkers and endothelial function. Finally, milk and dairy (M&D) products made from milk, except butter foods are the most important food groups for young children’s growth and development, and bone health. Yet, their use as a healthy food for children has been questioned because of the belief that their high fat content may contribute to excessive weight gain. Another objective of this project aims to investigate the effect of habitual M&D foods’ consumption on energy balance and whether they also have a protective effect against early cardiovascular and metabolic diseases. Overall this project will provide an enhanced understanding of how altered bone metabolism may contribute to long-term skeletal health and play a role in glucose metabolism and cardiovascular health in obese children. It will also provide evidence that habitually consuming M&D foods protect children against obesity and cardiometabolic disease.
Research Faculty: Fida Bacha
Decoding the Regulatory Molecular Interplay of Nutrition and Disordered Eating
Understanding the role of nutrition holds the key to decipher the causes and underpinning risk factors and comorbidities in early childhood development. Nutrient intake is closely intertwined with eating behavior. Several studies established the role of the Central Nervous System (CNS) in regulating food intake, and thereby controlling nutrition related disorders like obesity, diabetes, low bone density and other developmental conditions. The neuronal regulation of food intake in humans is well-appreciated, but our understanding of causal molecular events is limited. The interplay of diet and genome have advanced our understanding of feeding behavior from physiological aspects to a new molecular level. A comprehensive perspective of the underlying molecular phenomena requires interpretation of intricacy at multiple levels such as genome, transcriptome, epigenome proteome, and metabolome. With the advent of high-throughput techniques multi-omics data are widely available. However, large scale integrative platforms are limited in nutrition research. In this project, our research objective is to build a multi-omic data platform and create opportunities for integrated system-level approaches. Several studies established a link between nutrients and mRNA polymorphism (pre-mRNA splicing and alternative polyadenylation). However, mRNA polymorphism is poorly realized in eating disorders. This project aims to elucidate the molecular interplay of epigenome and transcriptome in aberrant eating behaviors using robust genome-wide computational analyses. Specifically, to conduct a multi-omic integrative study to systematically decipher the regulatory aspects of DNA methylation and histone modifications on alternative splicing and alternative polyadenylation in disordered eating. Novel machine learning approaches will be designed to address specific analytical challenges. The proposed integrative omics study will help to determine and reflect a deeper holistic view of the underlying molecular eating behavior control circuits and aid in identifying new nutritional and disease biomarkers, that are otherwise incomplete or not discovered by individual omics studies.
Research Faculty: Hari Krishna Yalamanchili
Effects of Sugary Drinks on Microbiome and Colon Cancer Development
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in developed countries. Epidemiological studies strongly suggest that diet is the most important environmental factor in CRC development. However, we still lack a clear understanding of the molecular and genetic underpinnings linking diet and CRC. Over the past four decades, an increasing number of studies have suggested a potential link between sugar consumption, especially in the form of sugary drinks, and CRC. Yet, the direct, causal link between the two has remained controversial. Our lab recently uncoupled the metabolic effects of sugary drinks from other confounding factors such obesity and diabetes by mimicking human consumption of sugary drinks in colon tumor mouse models in which Adenomatous polyposis coli (APC) (a tumor suppressor, was deleted. We found that the chronic consumption of a moderate amount of sugar in liquid directly increased both tumor size and number in an APC-driven mouse model. In this research plan, we hypothesize that sugary drinks contribute to CRC development by altering the composition and function of gut microbiota. To test our hypothesis, our three specific aims are to examine the tumorigenic effects of sugary drinks on an APC-driven colon tumor mouse model in which a human microbiome has been established through fecal microbiota transplantation; investigate the effects of sugary drinks on gut microbiota and microbial metabolism in this humanized mouse model; and determine the role of sugar-induced gut microbiota in CRC development. Successful completion of this project will uncover the molecular basis of interrelationships among dietary sugar, gut microbiota, and CRC development and identify sugar-induced metabolites and/or microbes that can serve as new biomarkers and targets for CRC patients. Moreover, we will provide science-based dietary guidance to the public and cancer patients, improving quality of life and prevent CRC diseases.
Research Faculty: Jihye Yun