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大量的假定机制， 范围从心外（例如，容量和压力超负荷，动脉粥样硬化，炎症， 神经体液环境）到心脏内（例如，离子稳态、信号传导和代谢）扰动。 关于该应用，先前的研究已经表明，“代谢可吸收性”（即，无法 适当地改变代谢以响应生理刺激或病理应激）起着关键作用。 在肥胖心肌病发展中的作用，通过促进能量不足， 代谢物积累、受损的信号传导和不利的重塑。我们小组以前的研究 揭示了正常心肌在一天中表现出很强的代谢灵活性， 在脂肪酸、葡萄糖和蛋白质代谢水平观察。此外，我们的研究表明， 这些代谢振荡主要由心肌细胞内的内在机制协调， 就像生物钟一样与目前的教条相反，我们观察到心脏的昼夜差异， 肥胖期间的代谢（即，保持代谢灵活性），这似乎有助于肥胖- 诱导的心脏脂肪变性、不良重塑和收缩功能障碍。这些意见强调， 确定心肌细胞生物钟和心脏节律之间的机制联系的重要性 无偏的转录组学和生物信息学方法表明，E4 BP 4（一个时钟控制的 转录因子）是可能的候选者。与E4 BP 4调节心脏代谢一致，我们的 未发表的初步数据显示，心肌细胞特异性E4 BP 4敲除小鼠心脏表现出 增强脂肪酸氧化。重要的是，E4 BP 4可以通过使用REV-1抑制。 ERBα/β激动剂。总的来说，这些观察导致了一个总体假设，即时间 肥胖期间心脏代谢的控制在心脏的不良重塑中起着因果作用。 抑制生物钟控制的E4 BP 4可减轻肥胖性心肌病 发展为了检验这一假设，提出了三个具体目标。具体目标1。完全定义 肥胖时心脏24小时代谢节律。具体目标2。将E4 BP 4建立为机械链接 心肌细胞生物钟和心脏代谢的时间分配之间的关系。具体目标3。 研究E4 BP 4的遗传和/或药理学抑制是否减弱肥胖的发病机制 心肌病成功完成拟议的研究将挑战目前的教条， 代谢灵活性和昼夜节律总是有益的，但相反， 肥胖引起的心功能不全的病因。此外，这些研究可能会强调 E4 BP 4作为降低肥胖患者心力衰竭风险的有益靶点

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.