Dietary and exercise interventions improve cognition and alter hippocampal transcriptomics in a mouse model of the metabolic syndrome

Metabolic syndrome (MetS) is a major global health concern that continues to rise in prevalence and further augments disease burden by predisposing individuals to cognitive impairment (CI). Managing MetS through lifestyle habits or interventions may prevent or improve CI. The ketogenic diet (KD) has garnered interest, but its long-term efficacy in preventing CI remains unknown, as does the optimal regimen in individuals that have already developed MetS. Herein, in a preventative paradigm in mice, we evaluated the ability of relatively long-term KD to prevent CI versus a Western-style high-fat diet (HFD) that induces MetS and CI. In an intervention paradigm to mice that had already developed MetS and CI, we compared the efficacy of low-fat standard diet intervention (SDI), KD intervention (KDI), exercise intervention (EXI), and combined KD-exercise intervention (KDI-EXI). We found that KD more effectively managed metabolism and prevented CI versus HFD. Among interventions, SDI, KDI, and KDI-EXI outperformed EXI, suggesting that dietary regimens universally surpass exercise alone in ameliorating HFD-induced MetS and CI. In tandem, to gain molecular insight, we profiled gene expression, and HFD hippocampus differed from other groups particularly in metabolic and neuroactive ligand-receptor signaling pathways. Overall, our findings have important health implications and especially advocate dietary strategies for preventing or improving MetS and associated CI.