Ketohexokinase-dependent metabolism of cerebral endogenous fructose in microglia drives diabetes-associated cognitive dysfunction

Boosted endogenous fructose production and metabolism in the hippocampus of db/db mice

Periodic measurements of cognitive status demonstrated marked and persistent cognitive dysfunction in db/db mice compared with the m/m mice at 24 weeks (Supplementary Fig. 1). Consequently, widely targeted metabolomic analysis was performed on serum and hippocampus to systematically analyze metabolic changes between db/db mice and m/m mice at that age. A total of 481 metabolites were identified by serum metabolomics analysis, including 190 upregulated and 49 downregulated metabolites (fold change (FC) > 1.2 or < 0.83, variable importance in projection (VIP) > 1 and P < 0.05) (Supplementary Fig. 2a). In the hippocampus, 526 metabolites were identified, including 182 upregulated and 89 downregulated metabolites (Supplementary Fig. 2b). Among them, glucose levels were upregulated in both…

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