Childhood obesity and related long-term effects are serious public health problems, but not all children with obesity do well in treatment. This study will test a new combination of family-based behavioral treatment (FBT) with a drug intervention using a glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide once weekly extended-release (ExQW, Bydureon®) in order to improve obesity intervention outcomes in 10-12-year-old children.

Using functional and structural magnetic resonance neuroimaging, this study will evaluate brain factors which could undermine treatment responses and long-term obesity intervention outcomes. Specific Aim 1 will test the effect of adding ExQW 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 its extent is related to immediate and/or long-term intervention outcomes.

Study Design: This double-blinded, randomized, placebo-controlled research study uses fMRI to characterize neural responses to a test meal before and at the end of FBT intervention, with vs. without additional GLP-1RA intervention. In addition, it uses structural MRI (sMRI) to test if MBH gliosis is reversible and/or associated with intervention outcomes.

Inclusion Criteria:

• 10-12 years of age
• Male or female
• Ability and willingness to participate in study visits including fMRI scans, blood draws, and weekly injections;
• Parent willing to provide informed written consent and child willing to provide written assent;
• Child has BMI z-score >95th percentile. for age and sex;
• One parent that is obese or overweight (BMI >27 kg/m2); willingness of 1 parent (does not have to be the parent with obesity) to engage in weekly family-based weight control treatment delivered in English.

Exclusion Criteria:

• History of acute or chronic serious medical conditions;
• known diabetes mellitus or recent (6 mo.) history of anemia;
• Presence of any implanted metal or metal devices, including ferro-metallic surgical clips or orthodontic braces;
• Claustrophobia;
• Documented cognitive disorder, disruptive behavior, inability to participate in group sessions;
• Current use of medications known to alter appetite, body weight, or brain response
• Food intolerance to test meal (macaroni and cheese) or vegetarianism/veganism or severe food allergies.
• Known renal impairment (GFR<60 ml/min/1.73m2)
• History of gastroparesis, pancreatitis or gallstones (unless status post cholecystectomy);
• Family history of multiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma;
• Known elevated calcitonin level at phone screening or increased measured calcitonin level at study visits;
• Untreated thyroid disorder or adrenal insufficiency;
• Use of weight loss medications (child participant) within 3 months of screening visit.
• Participating parent is pregnant