Brain and Obesity Longitudinal Development: Neurobiological Mechanisms of Semaglutide Treatment of Adolescent Obesity

Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide are increasingly prescribed to adolescents with obesity, but their effects on the developing adolescent brain are not well understood. This observational pilot study uses a within-subject, pre-post design to characterize the neurobiological, cognitive, behavioral, and biological changes associated with approximately 6 months of clinically prescribed semaglutide in adolescents. Participants are adolescents 12 to 15 years old with obesity whose treating physician has independently decided to initiate weekly subcutaneous semaglutide. Participants are enrolled before medication initiation and complete a baseline visit and a follow-up visit approximately 6 months later. The study team does not influence prescribing or dosing. Specific Aims: Aim 1 (Neuroimaging): Characterize within-subject changes in resting-state functional connectivity and brain structure (including hypothalamic and reward-network measures) before and after approximately 6 months of treatment, and compare these measures with normative data from the ABCD Study. Aim 2 (Neurobehavioral and biological markers): Measure changes in cognition, mood, interoceptive awareness, eating behavior, food-related reward and "food noise," and a panel of salivary and blood-based biomarkers (including adipokines, inflammatory markers, and neurotrophic and appetite-regulating factors), with biobanking for future analyses. Aim 3 (Qualitative): Characterize adolescents' lived experience of treatment through a semi-structured interview at follow-up. Assessments at each visit include 3T structural MRI, resting-state functional MRI, and dedicated hypothalamic (sella) imaging; a neurobehavioral and interoceptive battery administered to the adolescent along with selected parent-report measures; anthropometrics; and saliva and fasting blood collection for biomarker measurement and biobanking. Routine-type laboratory measures (e.g., HbA1c, ALT, lipids) are assayed on the research blood sample. Target enrollment is approximately 8 evaluable participants, with over-enrollment (up to approximately 12) to account for attrition; participants who withdraw before the follow-up visit may be replaced. Total participation is approximately 6 to 7 months. This study is funded by a Natalie V. Zucker Research Center Award at Tufts University School of Medicine.