Intermittent fasting attenuates obesity-related atrial fibrillation via SIRT3-mediated insulin resistance mitigation
Intermittent fasting attenuates obesity-related atrial fibrillation via SIRT3-mediated insulin resistance mitigation
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间歇性禁食通过 SIRT3 介导的胰岛素抵抗减轻减轻肥胖相关的心房颤动
DOI：
10.1016/j.bbadis.2023.166638
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Qiangsun Zheng
中科院分区：
文献类型：
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作者：
Yudi Zhang;Feng Gao;Haoyu Gong;Yuping Fu;Binghua Liu;Xinghua Qin;Qiangsun Zheng
目的房颤是最常见的快速性心律失常，亟待优化治疗。肥胖可导致房颤，其发病机制与胰岛素抵抗(IR)密切相关，但其机制治疗尚不够深入。间歇性禁食(IF)是一种新的生活方式干预措施，可以缓解IR，这是一种潜在的房颤驱动因素，但IF能否预防肥胖相关的房颤仍然难以捉摸。我们的目的是评价短期IF对房颤的影响，并揭示其潜在的机制。方法将肥胖小鼠(高脂饮食8周)置于IF(隔日禁食5周)以评估房颤易感性和底物形成，并将类似处理的新生心房心肌细胞(NRCM)和成纤维细胞(NRCFs)(棕榈酸盐，200UμM)与IF(隔日短期饥饿8天)进行机制研究。IF降低了房颤的诱导性、持续时间，逆转了肥胖小鼠的心房重构，包括通道障碍、左房扩张、心肌肥厚和纤维化，与体重减轻无关。在机制上，如果在体内和体外上调SIRT3蛋白水平，药物抑制(3-(1H-1，2，3-三氮唑-4-基)吡啶，50μM)和基因抑制SIRT3可以减弱IF介导的抗肥厚和纤维化的益处。此外，在肥胖小鼠和棕榈酸酯处理的细胞中，如果激活SIRT3的两个正向下游靶子AMPK和AKT信号，以及失活SIRT3的负下游靶子α信号，而抑制SIRT3则逆转了这些作用。结论IF通过SIRT3介导的IR缓解预防肥胖相关的房颤，从而代表了一种改善房颤管理的可行的生活方式干预。
ObjectiveAtrial fibrillation (AF) is the most common tachyarrhythmia in urgent need of therapeutic optimization. Obesity engenders AF, and its pathogenesis is closely intertwined with insulin resistance (IR), but mechanism-based management is still underinvestigated. Intermittent fasting (IF) is a novel lifestyle intervention that mitigates IR, a potential AF driver, yet whether IF can prevent obesity-related AF remains elusive. Here, we aimed to evaluate the impacts of short-term IF on AF and to uncover the underlying mechanism.MethodsWe subjected obese mice (high-fat diet for 8-week) to IF (alternative-day fasting for another 5-week) for AF vulnerability and substrate formation assessment, and similarly treated neonatal atrial cardiomyocytes (NRCMs) and fibroblasts (NRCFs) (palmitate, 200 μM) with IF (alternative-day short-term starvation for 8-day) for mechanism investigation.ResultsObese mice were prone to AF and atrial remodeling. IF reduced AF inducibility, duration, and reversed atrial remodeling including channel disturbance, left atrial dilation, cardiac hypertrophy and fibrosis in obese mice independent of weight loss. Mechanistically, IF up-regulated the SIRT3 protein level both in vivo and in vitro, and pharmacologic inhibition (3-(1H-1,2,3-Triazol-4-yl) pyridine, 50 μM) and genetic suppression of SIRT3 could attenuate the IF-mediated benefits against hypertrophy and fibrosis. Furthermore, IF activated AMPK and Akt signaling, two positive downstream targets of SIRT3, and inactivated HIF1α signaling, a negative downstream target of SIRT3 in both obese mice atria and palmitate-treated cells, while inhibition of SIRT3 reversed these effects.ConclusionIF prevents obesity-related AF via SIRT3-mediated IR mitigation, thus representing a feasible lifestyle intervention to improve AF management.