Dietary and exercise interventions improve cognition and alter hippocampal transcriptome in a metabolic syndrome mouse model

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. The 11-week-old male C57BL/6J mice were purchased from Jackson Laboratory. For the study, all mice were singly housed, given access to food and water ad libitum, and maintained on a 12:12 h light/dark cycle. At 12 weeks of age, mice were randomly assigned to seven groups: (i) standard diet (SD; n=16) mice maintained until 26 weeks of age on SD (10 kcal% fat;), (ii) HFD mice maintained until 26 weeks of age on lard-based HFD (60 kcal% fat), (iii) KD mice maintained until 26 weeks of age on cocoa butter-based KD (90% kcal% fat), (iv) DR mice fed HFD until 18 weeks of age and then switched to SD from 18 to 26 weeks of age, (v) KDI mice fed HFD until 18 weeks of age and then switched to KD from 18 to 26 weeks of age, (vi) EX mice fed HFD until 26 weeks of age and then provided full access to a voluntary running wheel from 18 to 26 weeks of age, (vii) KDI-EX mice fed HFD until 18 weeks of age and then switched to KD with full access to a running wheel from 18 to 26 weeks of age.At study end, mice were sacrificed and hippocampus tissue were collected for RNA sequencing.