Neural and behavioral mechanisms of obesity development from infancy through childhood

PROJECT SUMMARY Obesity risk shows individual variation such that some children are more likely than others to gain excess weight. One potential reason is that, due to genetic and environmental factors, individuals vary in appetitive behaviors that drive food intake and weight. However, the neurodevelopmental mechanisms underpinning variation in appetite and weight, and effects of risk and protective factors on those outcomes, are not understood. Preliminary data from RESONANCE, our large MRI cohort, suggests obesity risk factors (maternal pre- pregnancy obesity, obesity-associated genetic variants) are associated with not just heightened parent-reported child appetite and BMIz, but with slower global myelination, decreased gray matter volume within fronto-cingulate control circuits, and increased volume in striatal reward regions, from infancy through early childhood. However the relevance of these findings to appetitive behaviors and development of obesity in middle childhood is unknown. This is important because obesity rates and metabolic complications increase through development, adiposity and eating habits measured in later childhood track into adulthood, and obesity is harder to treat later in development, making middle childhood a key stage for capturing outcomes with relevance for lifetime metabolic health. Further, although task fMRI studies have identified altered patterns of activation in brain appetite circuits in association with pediatric obesity and early risk factors for obesity, the predictors of altered functioning of brain appetite circuits in middle childhood are unknown. Identifying the patterns of brain development that predict obesity-promoting behaviors and brain functioning in middle childhood is essential to understand the neural mechanisms by which early obesity risk factors drive excess intake and obesity, and may help pinpoint neurobehavioral targets for early obesity prevention. Finally, although preclinical research and MRI studies of children >9y support that hypothalamic gliosis, a cellular inflammatory response, plays a role in obesity pathogenesis, it is unclear whether it occurs or impacts appetite in earlier life. For the proposed study, RESONATE, we will address the above research gaps by extending the RESONANCE study to administer meal tests, behavioral and fMRI tasks assessing food and non-food reward and cognitive control, and weight/adiposity measures in middle childhood, and examining hypothalamic gliosis, in a sub-sample of RESONANCE children. By combining this data with extant MRI data and extant or newly-collected data on obesity risk and protective factors, we will test a multi-faceted hypothesis that prenatal, genetic and postnatal factors lead to differential early development of brain appetite circuits, which in turn gives rise to variation in appetitive behaviors and behaviors involving reward processing and cognitive control as well as altered function of brain appetite circuits, that act to influence the development of obesity into middle childhood. Our long-term goal is to lay foundations for developmentally-appropriate, neurobehaviorally-informed interventions to address child obesity.