Effects of prenatal exposures to maternal obesity and gestational diabetes on metabolic decline from childhood to adolescence and underlying neurobiological pathways

Parent Project Abstract Rising childhood obesity rates are coupled with an alarming increase in the prevalence of type 2 diabetes in children and adolescents. Evidence suggests that in utero exposures to maternal obesity and/or gestational diabetes mellitus (GDM) contribute to these upward trends, and the effects of these prenatal exposures on metabolic risk become more pronounced during adolescence. While the biological mechanisms of such maternal-fetal programming are poorly understood, compelling studies in rodent models show that in utero exposure to maternal obesity and/or diabetes causes abnormal development of brain pathways involved in energy balance regulation, leading to obesity and type 2 diabetes later in life. Our group was the first to study the effects in utero exposures to maternal obesity and GDM on brain pathways and metabolic outcomes in humans using a pioneering approach combining neuroimaging methods and metabolic phenotyping in children. To date, findings from our BrainChild cohort provide strong support for the neuroendocrine programming effects seen in animal models. The earliest abnormality we have identified involves modification of brain pathways known to be involved in energy balance regulation. These brain modifications were predictive of increases in food intake and weight gain in children during follow-up and support the primary hypothesis of the longitudinal BrainChild study: that differences in the neural markers observed in children at age 7-10 will be predictive of metabolic outcomes during the transition to adolescence, a critical time for brain development and metabolic decline. The longitudinal Brainchild study, with follow-up to 18 years, provides the unique opportunity to advance our understanding of the interplay among brain changes, obesity, insulin resistance and beta cell function at early stages in the evolution of transgenerational transmission of obesity and diabetes risks. Given the growing number of pregnancies complicated by maternal obesity and GDM, the well-being of future generations may depend to an important degree on developing interventions that can break the vicious transgenerational cycle of obesity and diabetes. The proposed studies will contribute critical information to the knowledge base required for development of such interventions. Aim 1: Examine relationships between in utero exposures to GDM and/or obesity and metabolic outcomes in offspring. Aim 2: Determine whether neural markers associated with in utero exposures to GDM and/or obesity will change and will be predictive of metabolic decline in offspring. Aim 3: Assess whether alteration(s) in neural markers involved in energy balance regulation is a pathway linking in utero exposure to GDM and/or obesity to metabolic decline during childhood to adolescence.