PROJECT SUMMARY Childhood obesity rate has been increasing dramatically, at great cost for health care and wellbeing. It is highly likely that obesity will persist into adulthood; thus, identifying risk factors contributing to childhood obesity is extremely critical so that prevention strategies can be taken early to reduce the obesity rate. Research suggests that children who were exposed to gestational diabetes mellitus (GDM) in utero have increased propensity of developing obesity. However, there are few human studies aimed to understand the mechanisms explaining this relationship. The goal of this study is to test the hypothesis that in utero exposure to GDM leads to abnormal development of brain pathways that regulate eating behavior, which in turn increases food intake and risk for obesity in children. To accomplish this goal, the applicant and her team plan to 1) examine effects of GDM on food intake; 2) associations of GDM exposure with structural and functional connections between brain appetite and reward pathways; 3) explore whether changes in brain circuitry involved in feeding behavior would mediate the link between GDM exposure and increased food intake thus increasing risk for obesity. This will be the first study in humans to use multi-modal imaging techniques to examine neural mechanisms of the link between GDM exposure and obesity risk. Through extensive mentor-directed training, course work and workshops, manuscript and grant writings, scientific presentations at national conferences, the candidate will achieve three training goals 1) strengthen knowledge about GDM physiology, pediatric obesity and nutrition in children (co-mentor Dr. Kathleen Page); 2) build skills in multi-modal imaging, and learn computational methods (e.g., psychological-physiological-interaction, independent component analysis, DTI fiber tracking, graph theory) to analyze functional and structural connectivity data under supervision of Drs. Paul Thompson (primary mentor) and Neda Jahanshad (co-mentor); 3) strengthen skills in advanced statistical modeling (e.g., mediation analysis) (co-mentor Dr. Anny Xiang). By the end of the proposed training period, the candidate will be positioned uniquely as a leader in investigating neural mechanisms for obesity risk in children exposed to maternal diabetes in utero with skills from various disciplines, and compete for an independent R01 application. Furthermore, this proposed project will help the candidate progress towards achieving her long-term career goal, which is to become an independent and innovative research scientist dedicated to investigating underlying mechanisms of obesity from a joint perspective of neuroscience, psychology and endocrinology.

PROJECT NARRATIVE Identifying both structural and functional abnormalities in connections between brain appetite and reward pathways among children exposed to gestational diabetes mellitus (GDM) in utero may provide a mechanistic understanding of the link between intrauterine exposure to GDM and increased obesity risk. This work will ultimately inform prevention strategies on attenuating alterations in fetal development of brain appetite and reward circuitry, and thereby reducing the risk of obesity in offspring. Given the vast health costs associated with obesity, knowledge gained from this study could offset the burden associated with obesity.