Dietary fructose promotes anxiety through impairment of microglia physiology

Excessive dietary fructose has been linked to metabolic and mood disorders but the underlying brain mechanisms remain unclear. In this study, we tested whether microglia, the brain resident immune cells, mediate fructose-induced anxiety. Adult C57BL/6J mice and mice knock-down for the fructose transporter Glut5 selectively in microglia (Slc2a5flox/flox:Tmem119-Cre-positive mice) were exposed to 25% fructose in drinking water for 8 weeks. We assessed metabolic parameters, anxiety- and depression-like behaviors using a battery of behavioral tests. We then performed RNA sequencing in several brain regions, including the hippocampus to characterize fructose-induced transcriptional changes. Microglial responsiveness to lipopolysaccharide (LPS) treatment was assessed in vitro and in vivo using immunohistochemistry (microglia morphology) and RT-qPCR (cytokine gene expression). Fructose feeding induced marked metabolic alterations and robust anxiety-like behavior in male mice, together with memory deficits, whereas females showed milder metabolic changes and memory impairment without clear emotional disturbances. RNA sequencing revealed that fructose alters microglial gene-expression profiles in the hippocampus. Microglial Glut5 knockdown prevented fructose-induced anxiety-like behavior in the novelty-suppressed feeding test, indicating that microglial fructose uptake is required for this effect. At the molecular level, physiological fructose exposure did not markedly increase microglial cytokine expression but blunted the cytokine response to lipopolysaccharide, consistent with a hypo-reactive microglial state. Overall, these findings identify microglia as a critical mediator of fructose-induced anxiety and suggest that chronic fructose exposure promotes a maladaptive microglial phenotype that disrupts brain circuit function, with potential implications for diet-related mental health risk.