Exercise mitigates the effects of a cafeteria diet on antidepressant-like behavior associated with plasma and microbial metabolites in adult male rats

A cafeteria diet high in saturated fat and sugar has been associated with increased anxiety-like and depressive-like behaviors and memory impairments, whereas exercise has been shown to promote antidepressant-like effects and enhance cognitive function in rodents. The mechanisms underlying the interactions between diet and exercise on mood, anxiety, and memory are not fully understood, but alterations in adult hippocampal neurogenesis (AHN), gut-derived metabolites, or plasma metabolic hormones may play a role. This study investigated whether voluntary exercise could mitigate the effects of concurrent exposure to a cafeteria diet on depression-like, anxiety-like, and cognitive behaviors in young adult male rats. Associated changes in AHN, metabolic hormones, and gut-derived metabolites were examined to identify potential mediators of behavioral changes. We found that exercise mitigated the cafeteria diet–induced increase in immobility in the forced swim test. This antidepressant-like effect of exercise in rats exposed to a cafeteria diet was accompanied by an attenuation of cafeteria diet–induced changes in plasma insulin and leptin, as well as in the abundance of caecal metabolites anserine, indole-3-carboxylate, and deoxyinosine. Exercise modestly improved spatial learning in the Morris water maze, promoted AHN and increased circulating levels of GLP-1, and these effects were blunted in animals exposed to a cafeteria diet suggesting that dietary composition plays a role in modulating the effects of exercise. Correlation analyses revealed that specific caecal metabolites were associated with depression- and cognition-related behaviors, independent of diet and exercise, highlighting the potential role of gut-derived metabolites in antidepressant-like behavior and cognitive function. Together these findings provide insight into potential metabolite and hormone-mediated mechanisms underlying the effects of a cafeteria diet and exercise on brain and behavior.