This study investigated the effects of a high-fat diet (HFD), particulate matter (PM) exposure, and resistance exercise training on circulating lipid profiles, adipokines, inflammatory responses, neurotrophic factors, and blood–brain barrier (BBB) permeability. Forty-eight 10-week-old male C57BL/6 mice were randomly assigned to four groups (
n = 12 per group): normal diet (ND), HFD, HFD with PM exposure (HFD + PM), and HFD with PM exposure plus exercise training (HFD + PM + EX). ND and HFD were administered for 16 weeks, whereas PM exposure and exercise training interventions were initiated after 8 weeks of dietary treatment and continued for an additional 8 weeks. PM was administered via tail vein injection three times per week, and resistance exercise training consisted of a ladder-climbing exercise performed five times per week. The results indicated that body weight, total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), leptin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), S100 calcium-binding protein B (S100B), and neuron-specific enolase (NSE) levels were significantly higher in the HFD group than in the ND group (
p < 0.05), whereas adiponectin and brain-derived neurotrophic factor (BDNF) levels were significantly lower (
p < 0.05). In addition, the HFD + PM group exhibited significantly lower BDNF and vascular endothelial growth factor (VEGF) levels (
p < 0.05) and significantly higher S100B and NSE levels (
p < 0.05) than the HFD group. In contrast, the HFD + PM + EX group showed significantly lower TG, LDL-C, leptin, and IL-6 levels than the HFD group (
p < 0.05). Moreover, compared with the HFD + PM group, the HFD + PM + EX group demonstrated significantly lower TG, LDL-C, leptin, S100B, and NSE levels (
p < 0.05) and significantly higher high-density lipoprotein cholesterol (HDL-C), adiponectin, BDNF, and VEGF levels (
p < 0.05). Collectively, these findings suggest that an HFD may contribute to dyslipidemia, heightened inflammatory responses, downregulation of neurotrophic factors, and increased BBB permeability and that concurrent PM exposure under HFD conditions may exacerbate adverse alterations in neurotrophic factors and BBB permeability. The results indicate that an HFD induces metabolic and neurovascular alterations, whereas concurrent PM exposure under HFD conditions is associated with additional changes in neurotrophic factors and BBB-related markers. Resistance exercise training attenuated these changes.
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