ABSTRACT/PROJECT SUMMARY The overarching goal of this proposal is to facilitate mentored training of junior investigators in the conduct of high-quality translational research into prevention of cardiometabolic disease. The PI is now Professor of Medicine at the University of Washington and guides a research program that is focused on the neurobiological basis of obesity, diabetes, and cardiovascular disease risk. The current proposal broadens the impact of this work by extending the existing program toward research focusing on understanding neurobiological factors that promote health, particularly in young children. It investigates the mechanistic basis of preventive dietary strategies that could alter trajectories of adiposity gain and ultimately reduce risk of cardiometabolic disease over the lifespan. The candidate’s background includes productive research mentorship of Fellows and junior faculty clinician-investigators, including K awardees. During this award, the PI will mentor a spectrum of trainees from fields including endocrinology and metabolism, pediatrics, and nutrition. The PI will take didactic mentoring courses and engage with experienced senior investigators to build skills necessary for the conduct of the research. The PI’s research program is currently focused on translational studies of cellular processes consistent with possible damage to the primary body-weight and glucose-regulating region of the hypothalamus—the arcuate nucleus. Studies in rodent models show that diet-induced weight gain is dependent on an inflammatory cellular response, known as gliosis, within the arcuate nucleus of the hypothalamus. Importantly, the PI has shown that gliosis is detectable in mice and humans by magnetic resonance imaging (MRI). Using MRI, the PI discovered the first evidence of hypothalamic gliosis in humans with obesity. The PI and trainees have shown that hypothalamic gliosis 1) is independently related to insulin resistance and type 2 diabetes in humans, 2) correlates with increased levels of visceral fat, 3) is present in children with obesity, and 4) predicts adiposity gain in children as well as worsening insulin sensitivity in adults. Funded projects investigate dietary antecedents of hypothalamic gliosis and its reversal by obesity treatment. The proposed research pivots toward an emphasis on prevention and intervention strategies that have the potential to modify the underlying neurobiological processes that drive cardiometabolic risk in obesity. Aim 1 tests the effect of high diet quality feeding on a radiologic marker of hypothalamic gliosis in children. Aim 2 evaluates the feasibility and acceptability of feeding intervention strategies that improve diet quality for low-income families with children with overweight or obesity. Completion of the Aims could provide fundamental insights into the central nervous system’s role in preserving cardiometabolic health and lay the groundwork for future intervention studies in pediatric...