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 Consistent with E4BP4 regulating cardiac metabolism, our unpublished preliminary data reveal that cardiomyocyte-specific E4BP4 knockout mouse hearts exhibit augmented fatty acid oxidation.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- ERB?/? 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.
Recent studies from our group have revealed that circadian clock-mediated oscillations in myocardial glucose, fatty acid, and protein metabolism are essential for maintenance of normal cardiac function. Here, we will test the hypothesis that alteration of daily metabolic oscillations in the heart contributes to the pathogenesis of heart dysfunction during obesity. Successful completion of the proposed studies will lead to new fundamental insights regarding the causal role of circadian perturbations in the etiology obesity cardiomyopathy, and will highlight targeting of circadian clock function as a salutary approach for reducing the risk of heart failure.