Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
FASEB J. 2021 Mar;35(3):e21298. doi: 10.1096/fj.202001706RR.
An intrinsic property of the heart is an ability to rapidly and coordinately adjust flux through metabolic pathways in response to physiologic stimuli (termed metabolic flexibility). Cardiac metabolism also fluctuates across the 24-hours day, in association with diurnal sleep-wake and fasting-feeding cycles. Although loss of metabolic flexibility has been proposed to play a causal role in the pathogenesis of cardiac disease, it is currently unknown whether day-night variations in cardiac metabolism are altered during disease states. Here, we tested the hypothesis that diet-induced obesity disrupts cardiac "diurnal metabolic flexibility", which is normalized by time-of-day-restricted feeding. Chronic high fat feeding (20-wk)-induced obesity in mice, abolished diurnal rhythms in whole body metabolic flexibility, and increased markers of adverse cardiac remodeling (hypertrophy, fibrosis, and steatosis). RNAseq analysis revealed that 24-hours rhythms in the cardiac transcriptome were dramatically altered during obesity; only 22% of rhythmic transcripts in control hearts were unaffected by obesity. However, day-night differences in cardiac substrate oxidation were essentially identical in control and high fat fed mice. In contrast, day-night differences in both cardiac triglyceride synthesis and lipidome were abolished during obesity. Next, a subset of obese mice (induced by 18-wks ad libitum high fat feeding) were allowed access to the high fat diet only during the 12-hours dark (active) phase, for a 2-wk period. Dark phase restricted feeding partially restored whole body metabolic flexibility, as well as day-night differences in cardiac triglyceride synthesis and lipidome. Moreover, this intervention partially reversed adverse cardiac remodeling in obese mice. Collectively, these studies reveal diurnal metabolic inflexibility of the heart during obesity specifically for nonoxidative lipid metabolism (but not for substrate oxidation), and that restricting food intake to the active period partially reverses obesity-induced cardiac lipid metabolism abnormalities and adverse remodeling of the heart.
心脏的固有特性是能够迅速协调地调节代谢途径中的通量，以响应生理刺激（称为代谢灵活性）。心脏代谢也会随着 24 小时昼夜的变化而波动，与昼夜睡眠-觉醒和禁食-喂养周期有关。尽管已经提出代谢灵活性的丧失在心脏病的发病机制中起因果作用，但目前尚不清楚在疾病状态下心脏代谢的昼夜变化是否会发生改变。在这里，我们检验了这样一个假设，即饮食诱导的肥胖会破坏心脏的“昼夜代谢灵活性”，而限时喂养会使其恢复正常。在小鼠中，慢性高脂肪喂养（20 周）引起的肥胖消除了全身代谢灵活性的昼夜节律，并增加了不良心脏重构的标志物（肥大、纤维化和脂肪变性）。RNAseq 分析显示，肥胖期间心脏转录组的 24 小时节律发生了巨大变化；在正常心脏中，只有 22%的节律性转录本不受肥胖影响。然而，在正常和高脂肪喂养的小鼠中，心脏底物氧化的昼夜差异基本相同。相比之下，肥胖期间心脏甘油三酯合成和脂质组的昼夜差异完全消失。接下来，一部分肥胖小鼠（通过 18 周自由摄入高脂肪饮食诱导）仅在暗（活动）期 12 小时内允许摄入高脂肪饮食，持续 2 周。暗期限时喂养部分恢复了全身代谢灵活性，以及心脏甘油三酯合成和脂质组的昼夜差异。此外，这种干预部分逆转了肥胖小鼠的不良心脏重构。总之，这些研究揭示了肥胖期间心脏的昼夜代谢灵活性丧失，特别是对非氧化脂质代谢（而不是对底物氧化），并且限制食物摄入到活动期部分逆转了肥胖引起的心脏脂质代谢异常和心脏的不良重构。
