Chronobiological Effects of Exercise on Brain Cholesterol Homeostasis, Endoplasmic Reticulum Stress Pathway and Aβ-42 Accumulation in the Hippocampus of HFD-Fed Mice
| Author | Asieh Sadat Mousavian | en |
| Author | Saied Shakerian | en |
| Author | Mohammad Reza Tabandeh | en |
| Author | Abdolhamid Habibi | en |
| Orcid | Asieh Sadat Mousavian [0000-0002-2615-3772] | en |
| Orcid | Saied Shakerian [0000-0002-0880-9942] | en |
| Orcid | Mohammad Reza Tabandeh [0000-0003-3258-8550] | en |
| Orcid | Abdolhamid Habibi [0000-0003-3407-2574] | en |
| Issued Date | 2025-06-30 | en |
| Abstract | Background: Diabetes disrupts hippocampal function and contributes to neurodegeneration. Physical exercise improves metabolic outcomes and exerts neuroprotective effects in diabetic conditions. Objectives: The chronobiological impact of exercise on brain cholesterol homeostasis, endoplasmic reticulum (ER) stress, and amyloid-beta (Aβ-42) processing remains poorly understood. This study aims to investigate the influence of exercise timing on these pathways in the hippocampus of diabetic high-fat diet (HFD)-fed mice. Methods: In this experimental study, 48 male laboratory mice were randomly divided into control, metabolic syndrome (MetS), and MetS + exercise groups. The MetS was induced via a 12-week HFD. All procedures were conducted under a controlled 12:12 light-dark cycle (lights on at 07:00 AM, off at 07:00 PM) to minimize circadian variability. Following MetS confirmation, mice in the exercise group underwent treadmill training for 8 weeks during early light or early dark phases (5 days/week, 60 - 80 minutes/day). Hippocampal expression of proteins related to cholesterol metabolism and Aβ processing was quantified by western blotting, and ER stress-related gene expression was assessed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Serum biochemical parameters were measured with commercial kits. Statistical analyses were performed using two-way analysis of variance (ANOVA) followed by Tukey’s post hoc test, with significance set at P < 0.05. Results: Twelve weeks of HFD significantly disrupted brain cholesterol metabolism, enhanced ER stress markers, and altered Aβ-related gene expression in the MetS group (P < 0.05). Eight weeks of exercise at both time points modulated the expression of CYP46A1, ATP-binding cassette transporter A1 (ABCA1), HMGCR, ATF6, PERK, and Aβ-42 (P < 0.05). Evening exercise specifically induced significant upregulation of glucose-regulated protein 78 (GRP78), PERK, low-density lipoprotein receptor (LDLR), SREBP2, and reduced serum cholesterol levels. Moreover, GRP78 and SREBP2 expressions were significantly higher following evening exercise compared to morning sessions (P < 0.05). Conclusions: These findings suggest that evening exercise may potentiate the metabolic benefits of physical activity by modulating circadian expression of SREBP2 and GRP78. This temporal modulation may contribute to improved cholesterol regulation and attenuated ER stress, potentially offering neuroprotective effects against neurodegenerative disorders. | en |
| DOI | https://doi.org/10.5812/jjcmb-162429 | en |
| Keyword | Continuous Exercise | en |
| Keyword | Brain Cholesterol | en |
| Keyword | Endoplasmic Reticulum Stress | en |
| Keyword | Beta-amyloid | en |
| Keyword | Metabolic Syndrome | en |
| Publisher | Brieflands | en |
| Title | Chronobiological Effects of Exercise on Brain Cholesterol Homeostasis, Endoplasmic Reticulum Stress Pathway and Aβ-42 Accumulation in the Hippocampus of HFD-Fed Mice | en |
| Type | Research Article | en |
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