Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FL.
Med Sci Sports Exerc. 2019 Oct;51(10):2012-2024. doi: 10.1249/MSS.0000000000002011.
Metabolic disorder such as obesity and type 2 diabetes caused by excess caloric intake is associated with an increased risk of neurodegenerative diseases. Endurance exercise (EXE) has been suggested to exert neuroprotective effects against the metabolic distress. However, the exact underlying molecular mechanisms responsible for the exercise-induced neuroprotection have not been fully elucidated. In this study, we investigated whether EXE-induced neuroprotection is associated with cellular senescence, neuroinflammation, and oxidative stress using a mouse model of obesity induced by a high-fat/high-fructose diet.
C57BL/6 female mice (10 wk old) were randomly divided to three groups: normal chow diet group (CON, n = 11), high-fat diet/high-fructose (HFD/HF) group (n = 11), and high-fat diet/high-fructose + endurance exercise (HFD/HF + EXE) group (n = 11). HFD/HF + EXE mice performed treadmill running exercise for 60 min·d, 5 d·wk for 12 wk.
Our data showed that EXE ameliorated HFD/HF-induced weight gain, fasting blood glucose levels, and visceral fat gain. More importantly, HFD/HF diet promoted cellular senescence, whereas EXE reversed it, evidenced by a reduction in the levels of p53, p21, p16, beta-galactosidase (SA-β-gal), and lipofuscin. Furthermore, EXE prevented HFD/HF-induced neuroinflammation (e.g., tumor necrosis factor-α and interleukin-1β) by inhibiting toll-like receptor 2 downstream signaling cascades (e.g., tumor necrosis factor receptor-associated factor 6, c-Jun N-terminal kinase, and c-Jun) in parallel with reduced reactive glial cells. This anti-inflammatory effect of EXE was associated with the reversion of HFD/HF-induced cellular oxidative stress.
Our study provides novel evidence that EXE-induced antisenescence against metabolic distress in the hippocampus may be a key neuroprotective mechanism, preventing neuroinflammation and oxidative stress.
过量热量摄入引起的代谢紊乱，如肥胖和 2 型糖尿病，与神经退行性疾病的风险增加有关。耐力运动（EXE）已被证明对代谢压力具有神经保护作用。然而，EXE 诱导的神经保护的确切潜在分子机制尚未完全阐明。在这项研究中，我们使用高脂肪/高果糖饮食诱导的肥胖小鼠模型，研究了 EXE 诱导的神经保护是否与细胞衰老、神经炎症和氧化应激有关。
将 10 周龄 C57BL/6 雌性小鼠随机分为三组：正常饲料组（CON，n = 11）、高脂肪饮食/高果糖（HFD/HF）组（n = 11）和高脂肪饮食/高果糖+耐力运动（HFD/HF + EXE）组（n = 11）。HFD/HF + EXE 组小鼠进行 12 周的跑步机跑步运动，每天 60 分钟，每周 5 天。
我们的数据表明，EXE 改善了 HFD/HF 引起的体重增加、空腹血糖水平和内脏脂肪增加。更重要的是，HFD/HF 饮食促进了细胞衰老，而 EXE 则逆转了这一过程，表现为 p53、p21、p16、β-半乳糖苷酶（SA-β-gal）和脂褐素水平降低。此外，EXE 通过抑制 Toll 样受体 2 下游信号级联（例如，肿瘤坏死因子受体相关因子 6、c-Jun N-末端激酶和 c-Jun），同时减少反应性神经胶质细胞，防止了 HFD/HF 引起的神经炎症（例如，肿瘤坏死因子-α和白细胞介素-1β）。EXE 的这种抗炎作用与 HFD/HF 诱导的细胞氧化应激的逆转有关。
本研究提供了新的证据，表明 EXE 诱导的代谢应激海马体抗衰老可能是一种关键的神经保护机制，可预防神经炎症和氧化应激。
