Metabolic Rhythm Alterations as a Cause for Obesity Cardiomyopathy

在肥胖性心肌病的发病机制中，已经提出了过多的可能机制， 范围从心外(例如，容量和压力过载、动脉粥样硬化、炎症和 神经体液环境)到心脏内(例如离子稳态、信号和新陈代谢)扰动。 关于这一应用，先前的研究表明，“代谢不灵活”(即不能 在应对生理刺激或病理性压力时适当改变新陈代谢)起着关键作用 在肥胖心肌病发展中的作用，通过引发能量不足，有害的 代谢物积聚，信号受损，和不利的重构。我们小组之前的研究 显示正常的心肌在一天的过程中表现出深刻的代谢灵活性， 观察脂肪酸、葡萄糖和蛋白质代谢水平。此外，我们的研究表明， 这些代谢振荡主要是由心肌细胞内的一种内在机制来协调的，众所周知 就像生物钟一样。与目前的教条相反，我们观察到心脏的强烈昼夜差异 肥胖期间的新陈代谢(即保持代谢灵活性)，这似乎有助于肥胖- 导致心脏脂肪变性、不良重构和收缩功能障碍。这些观察结果强调了 确定心肌细胞昼夜节律时钟和心脏功能之间的机制联系的重要性 新陈代谢；无偏见的转录学和生物信息学方法表明，E4BP4(一种时钟控制的 转录因子)是一个可能的候选者。与E4BP4调节心脏代谢一致，我们的 未发表的初步数据显示，心肌细胞特异的E4BP4基因敲除小鼠心脏表现出 增强脂肪酸氧化作用。重要的是，E4BP4可以通过使用REV-1被药物抑制。 ERBα/β激动剂。总而言之，这些观察结果导致了一个重要的假设，即 肥胖期间心脏代谢的调控在心脏不良重塑中起着因果作用 抑制钟控E4BP4减轻肥胖性心肌病 发展。为了验证这一假说，本文提出了三个具体目标。具体目标1.充分定义 肥胖期间心脏的24小时代谢节律。具体目标2.建立E4BP4作为机制纽带 心肌细胞生物钟和心脏代谢的时间分割之间的关系。具体目标3. 研究E4BP4基因和/或药物抑制是否减轻肥胖的发病机制 心肌病。拟议研究的成功完成将挑战目前的教条，即 新陈代谢的灵活性和昼夜节律总是有益的，但反而有助于 肥胖性心功能不全的病因。此外，这些研究可能会强调 E4BP4作为在肥胖环境中降低心力衰竭风险的有益目标。

A plethora of putative mechanisms have been proposed in the pathogenesis of obesity cardiomyopathy, ranging from extra-cardiac (e.g., volume and pressure overload, atherosclerosis, inflammation, and the neurohumoral environment) to intra-cardiac (e.g., ion homeostasis, signaling, and metabolism) perturbations. With respect to this application, prior studies have suggested that `metabolic inflexibility' (i.e., inability to appropriately alter metabolism in response to physiologic stimuli or pathologic stress) plays a pivotal role in obesity cardiomyopathy development, by precipitating energetic insufficiency, detrimental metabolite accumulation, impaired signaling, and adverse remodeling. Previous studies from our group revealed that the normal myocardium exhibits profound metabolic flexibility over the course of the day, observed at the levels of fatty acid, glucose, and protein metabolism. Furthermore, our studies indicate that these metabolic oscillations are orchestrated primarily by an intrinsic mechanism within cardiomyocytes, known as the circadian clock. Contrary to the current dogma, we observe robust day-night differences in cardiac metabolism during obesity (i.e., preserved metabolic flexibility), which appear to contribute towards obesity- induced cardiac steatosis, adverse remodeling, and contractile dysfunction. These observations underscore the importance of identifying mechanistic links between the cardiomyocyte circadian clock and cardiac metabolism; unbiased transcriptomic and bioinformatics approaches suggest that E4BP4 (a clock-controlled transcription factor) is a likely candidate. Consistent with E4BP4 regulating cardiac metabolism, our unpublished preliminary data reveal that cardiomyocyte-specific E4BP4 knockout mouse hearts exhibit augmented fatty acid oxidation. Importantly, E4BP4 can be pharmacologically repressed, through use of REV- ERBα/β agonists. Collectively, these observations have led to the overarching hypothesis that temporal governance of cardiac metabolism during obesity plays a causal role in adverse remodeling of the myocardium, and that repressing clock-controlled E4BP4 attenuates obesity cardiomyopathy development. In order to test this hypothesis, three Specific Aims are proposed. Specific Aim 1. Define fully 24-hr metabolic rhythms in the heart during obesity. Specific Aim 2. Establish E4BP4 as a mechanistic link between the cardiomyocyte circadian clock and temporal partitioning of cardiac metabolism. Specific Aim 3. Investigate whether genetic and/or pharmacologic repression of E4BP4 attenuates the pathogenesis of obesity cardiomyopathy. Successful completion of the proposed studies will challenge current dogmas that metabolic flexibility and circadian rhythms are invariably beneficial, but instead can contribute towards the etiology of obesity-induced cardiac dysfunction. Furthermore, these studies will likely highlight E4BP4 as a salutary target for reducing the risk of heart failure in the setting of obesity.