Neuroprotective effects of semaglutide targeting the left temporal lobe in adults with overweight or obesity: A 24‐week multimodal neuroimaging study

Abstract Background Since obesity and its associated metabolic dysregulation are recognized risk factors for cognitive decline, this study investigated whether semaglutide, a glucagon‐like peptide‐1 receptor agonist proven to have cardiometabolic benefits, could provide potential neuroprotective effects on brain structure and function. Methods In a prospective, single‐arm intervention study, 26 adults with overweight or obesity received 1.0 mg semaglutide weekly for 24 weeks. Multimodal assessments were performed pre‐ and post‐intervention, including structural and functional MRI for analysing grey matter volume (GMV), fractional amplitude of low‐frequency fluctuations (fALFF), and regional homogeneity (ReHo). Cognitive function was evaluated using standardized computerized tasks (the Flanker and N‐back). Additionally, comprehensive metabolic profiles were assessed, including markers of glucose and lipid metabolism along with inflammatory cells. Results Semaglutide treatment significantly improved systemic metabolic health, inducing weight loss and reducing glycolipid levels and leukocyte counts. Neuroimaging revealed targeted neurobiological effects in the left temporal lobe: specifically, increased GMV in the left inferior temporal gyrus and decreased fALFF in the left middle and superior temporal gyri alongside reduced ReHo in the left middle temporal gyrus. These neural changes occurred despite no significant improvement in cognitive task performance. Importantly, the alterations in brain structure and function were not statistically correlated with the degree of weight loss or metabolic improvement. Conclusions A 24‐week semaglutide intervention induces significant neurobiological remodelling in the left temporal lobe of adults with overweight or obesity. These central effects are independent of the drug's systemic metabolic improvements, offering new evidence for its potential neuroprotective role.