Metabolism, Nutrition and Development
Center Leaders: Babette Zemel, PhD and Rebecca Simmons, MD
Disorders of nutrition and metabolism affect the majority of patient populations cared for at Children’s Hospital. Failure-to-thrive, obesity and bone deficits are common complications in a wide variety of chronic conditions. Malabsorption, inflammation, reduced physical activity, altered dietary intake and medical treatments often have a profound effect on nutrient metabolism, growth, body composition, and health and disease outcomes. In addition, many of the major chronic diseases of adulthood, such as diabetes, hypertension, osteoporosis, cardiovascular disease and some cancers are nutrition-related and have antecedents in childhood.
The goal of the Metabolism, Nutrition and Development Affinity Group is to identify the causes and consequences of metabolic and nutritional disorders of childhood and to identify effective strategies for disease prevention and treatment. An additional goal is the prevention of obesity and nutrition related diseases in adulthood that have their origins in infancy and childhood.
The group boasts many multidisciplinary research projects across a wide range including gastroenterology, hepatology and nutrition, endocrinology, psychiatry, cardiology, hematology, nephrology, rheumatology, pulmonology, neurology, nursing, child development and neonatology. Obesity is a common theme across many of the specific areas of research. The obesity epidemic is a growing concern, and is increasingly becoming a problem in the pediatric patient population. Major research efforts include evaluation of behavioral and medical treatments for obese adolescents, practice-based obesity prevention and treatment, effect of obesity on bone strength, early life determinants of obesity and diabetes, prevention and treatment of diabetes, and the effect of obesity on sleep apnea, asthma and other pulmonary complications.
The State Tobacco Resettlement Act funded the project titled Risk Factors for the Pediatric Metabolic Syndrome to evaluate the contribution of obesity, obstructive sleep apnea, fasting insulin levels and family history of diabetes to overall glucose tolerance, insulin sensitivity, and lipid and blood pressure abnormalities. This study has shown relationships between disordered sleep, insulin resistance and other abnormalities associated with the metabolic syndrome such as lower adiponectin and HDL, and higher HbA1C and waist circumference. The State Tobacco Resettlement Act funds also support a new multi-center study of obesity led by Robert Berkowitz, MD, that provides office based obesity treatment in both urban and rural settings.
The research program led by Rebecca Simmons, PhD, is focused on elucidating the underlying molecular mechanisms that link the abnormal milieu of diabetic or obese pregnancies to the development of obesity and type 2 diabetes in offspring. Having developed a number of models of diabetes and/or obesity in pregnancy, Dr. Simmons' research has determined that this abnormal metabolic environment induces epigenetic modifications in key genes that regulate β-cell and adipocyte development. One study of newborns whose mothers had diabetes during pregnancy was conducted to determine whether diabetes in pregnancy alters genomic DNA methylation in genes important for regulating glucose homeostasis, and whether these epigenetic changes permanently alter gene expression, resulting in an adverse phenotype. To test this hypothesis investigators are using a novel technology to compare genome-wide cytosine methylation in amniocytes and in a single population of CD34+ cells derived from the cord blood of newborns of mothers who have diabetes.
Abnormalities of growth and body composition in children with chronic diseases are another major research theme in the Metabolism, Nutrition and Development Affinity Group. Various research projects are underway to describe the timing, magnitude, causes and consequences of growth failure and altered body composition in children with sickle cell disease, cystic fibrosis, Crohn disease, renal insufficiency, juvenile rheumatoid arthritis, Down syndrome, intractable epilepsy, liver disease, lupus erythymatosis and cardiac malformations. As part of a current ongoing collaboration, Barbara Medoff-Cooper, PhD, RN; Virginia Stallings, MD; and Babette Zemel, PhD, have identified patterns of growth failure in infants after cardiac surgery, demonstrating the need to develop nutritional care intervention strategies for these at-risk infants. Another set of collaborative studies, directed by Dr. Stallings and conducted over the past 15 years, have identified numerous nutritional deficiencies and potential treatment strategies for children with sickle cell disease. This series of studies has identified increased energy requirements, poor growth and delayed maturation, and deficiencies of zinc, vitamin D and vitamin A. A study on zinc supplementation demonstrated the benefits of this important nutrient for improved growth. Investigators are now studying vitamin A supplementation to determine the effect of improved vitamin A status on frequency of hospitalizations and sickle cell-related illness episodes.
Another major research focus is skeletal development and the effects of nutrition, inflammation and obesity on bone density, the attainment of peak bone mass and fractures. Mary Leonard, MD, MSCE; Sandy Burnham, MD; and Meena Thayu, MD, are conducting studies of children with renal, rheumatologic and gastrointestinal disorders to examine the effects of medication use, disease effects and physical activity on bone density and strength. Nicolas Stettler, MD, MSCE, has recently initiated a study of the effects of weight loss treatment on bone accrual in obese adolescents. Dr. Zemel has several studies of bone development in healthy children to improve our understanding of the normal patterns of development of the skeleton.
Another major focus of the RAG is to foster career development of junior investigators. We established the Pilot and Feasibility program, which is intended to provide support for both junior and established investigators to collect preliminary data sufficient to support a federal RO1 grant application for independent research support. We solicited submission of applications for support to perform pilot and feasibility studies in nutritional sciences, obesity and related disorders. To date, we have funded three projects. The first is a collaboration led by Myles Faith, PhD, Dr. Medoff-Cooper and other members of the affinity group to examine the genetics of feeding style and body composition in twin infants. Two new investigators, Andrea Kelly, MD, and Jon Burnham, MD, were recently awarded pilot grants.
These projects focused on determining whether vitamin D supplementation improves bone health in children with lupus and the effects of vitamin D supplementation on body composition and markers of inflammation in children with cystic fibrosis. The RAG has also provided funds for a study of vitamin D status in children with perinatally acquired HIV infection.
In addition, researchers in the affinity group investigate biliary atresia and bile duct development through the Fred and Suzanne Biesecker Center for Pediatric Liver Disease. Bringing together experts across hospital disciplines, such as gastroenterology, human genetics and pathology, the affinity group also partners with the adult liver program at the University of Pennsylvania.
Affinity group members participate in several seminar series to promote interdisciplinary interactions and generation of innovative lines of research. At Children’s Hospital these include the Nutrition Center Seminar Series and the Seminars of the Division of Pediatric Endocrinology. At the University of Pennsylvania RAG members attend the seminar series held by the Institute for Diabetes, Obesity and Metabolism, the Penn Center for Musculoskeletal Disorders, and the Center for Clinical Epidemiology and Biostatistics.