ABSTRACT: The metabolic syndrome (MetS) is a major global health concern that continues to rise in prevalence. Further fueling the burden of disease, MetS predisposes individuals to neural injury, enhancing the risk of developing cognitive impairment (CI). MetS management encourages weight loss and physical activity to ameliorate overall systemic metabolic health with consequent improvement on CI. In this light, diet and exercise (EX) have garnered interest as non-pharmacological interventions for CI, which, besides their salutary benefits on systemic metabolic health, exert multifactorial neuroprotective effects locally within neural tissue. Nevertheless, the detailed molecular and cellular mechanisms of diet- and EX-mediated benefits on CI remain incompletely understood. Moreover, most studies have assessed the impact of either diet or EX on CI, so direct, head-to-head comparisons are lacking, to our knowledge. Herein, we compared high-fat diet (HFD) and ketogenic diet (KD) versus standard-diet (SD) on systemic metabolism, CI, and hippocampus transcriptome. We also assessed the efficacy of dietary reversal (DR, switch from HFD to SD), KD intervention (KDI), EX, and combined KDI-EX for reversing HFD-induced MetS CI. We found HFD, but not KD, impaired systemic metabolism and induced CI relative to SD, and all diets differed in hippocampus transcriptome. All interventions, DR, KDI, EX, and KDI-EX improved the MetS and CI, albeit to differing extents with superior performance from diets with/without EX than EX alone. In tandem, interventions also changed hippocampal gene expression, in metabolic and neuroactive ligand-receptor signaling pathways. Overall, our findings have important health implications and especially advocate diet for improving MetS and associated CI.
