IMPACT OF SEMAGLUTIDE ON METABOLIC PROFILE AND HIPPOCAMPAL NEUROGENESIS IN HIGH-FAT/HIGH-SUGAR-FED YOUNG RATS

Obesity is linked to metabolic imbalance and hippocampal alterations, including impaired neurogenesis, contributing to cognitive deficits. Pediatric obesity is rising globally, yet pharmacological interventions remain limited in Europe. Semaglutide, a glucagon-like peptide-1 receptor agonist, shows neuroprotective effects in preclinical models; however, its impact on hippocampal structure and cognition in diet-induced obesity remains poorly characterized.
Thirty-six male Wistar Hannover rats (2 months old) were fed a control (CT, n=12) or high-fat/high-sugar (HFHS, n=24) diet for 8 weeks. Rats were then assigned to six groups (n=6/group) for 12-week interventions: CT, CT+semaglutide, HFHS, HFHS+diet normalization, HFHS+diet normalization+semaglutide, and HFHS+semaglutide. Body weight was monitored, anxiety and spatial memory were assessed using the plus maze and Morris water maze tests, and hippocampal neurogenesis was quantified by doublecortin (DCX) immunostaining in the subgranular layer of the dentate gyrus.
HFHS feeding induced weight gain, increased anxiety-like behavior, impaired spatial memory-recall in the probe trial, alongside reduced hippocampal DCX density. Semaglutide treatment, particularly when combined with dietary normalization, reversed weight gain, normalized anxiety and memory performance, and mitigated HFHS-induced reductions in DCX, restoring levels toward controls. Learning performance was largely unaffected, and semaglutide effects were more pronounced in metabolically challenged rats, while control rats showed only subtle behavioral changes.
These results indicate that semaglutide could exert some protection regarding hippocampal neurogenesis and cognitive function in diet-induced obesity. The findings support its potential for mitigating obesity-associated neurocognitive deficits and highlight the context-dependent neuroprotective action of GLP-1 receptor agonists.