PROJECT SUMMARY Given the high prevalence of childhood obesity in the U.S. and the lack of durable weight loss with existing obesity interventions, new options that improve pediatric weight management are needed. Intensive family-based behavioral treatment (FBT) is the gold-standard intervention for children with obesity and is focused on changing food environments and parenting around children's eating. The proposed research is a renewal of the Brain Activation and Satiety In Children (BASIC) study which used functional Magnetic Resonance Imaging (fMRI) to better understand if neurobiological factors impact success in FBT. In this study, 55% of children with obesity treated with FBT showed clinically significant reductions in BMI z-score, and even after successful treatment, over two-thirds of children increased their BMI z-score 6?12 months after ending FBT. At baseline pre-FBT, children with obesity, compared to children of healthy weight, exhibited an attenuated central response to a satiating meal in which they did not reduce activation by high-calorie food cues across a set of a priori appetite-regulating brain regions. This pattern also was associated with worse FBT outcomes among obese children undergoing FBT, specifically, less reduction in BMI z-score during treatment. Further, greater BMI z-score reduction during FBT was associated with a decreased neural satiety response after treatment. These findings implicate neurobiological factors as a negative input onto children's ability to achieve and maintain clinically significant improvement in weight status via FBT. The proposed follow-up project builds upon these findings and investigates the hypothesis that adding a glucagon-like peptide-1 receptor agonist (GLP-1RA) once weekly drug intervention to FBT will augment BMI z-score reduction, even among children who seem initially resistant to FBT, by promoting greater reductions in neural activation in response to a meal. In a double-blinded randomized placebo-controlled clinical trial among 64 children aged 10-12 years old, Specific Aim 1 will test the effect of adding GLP-1RA to FBT on change in BMI z-score over a total GLP-1RA treatment duration of 24 weeks and a subsequent 1-year observational follow-up period after treatment cessation. To provide mechanistic insight, Specific Aim 2 will test whether adding GLP-1RA intervention to FBT impacts neural activation by food cues. Finally, the proposed research will investigate the role of a cellular inflammatory process in the mediobasal hypothalamus ?called gliosis? which might contribute to impaired hypothalamic function, attenuated satiety responsiveness, and potentially to worse weight management outcomes. Specific Aim 3 will test if hypothalamic gliosis is modified by FBT and/or FBT plus GLP-1RA in children and if reduction of gliosis is associated with better long-term outcomes. This research builds upon the team's prior findings to test a pharmacologic intervention with potential to modify neurobiological barriers to treatment success. The long-term objective is to translate these findings to improve obesity interventions and sustain better long-term results.