Altered myocardial metabolic adaptation to increased fatty acid availability in cardiomyocyte-specific CLOCK mutant mice

Abstract

A mismatch between fatty acid availability and utilization leads to cellular/organ dysfunction during cardiometabolic disease states (e.g., obesity, diabetes mellitus). This can precipitate cardiac dysfunction. The heart adapts to increased fatty acid availability at transcriptional, translational, post-translational and metabolic levels, thereby attenuating cardiomyopathy development. We have previously reported that the cardiomyocyte circadian clock regulates transcriptional responsiveness of the heart to acute increases in fatty acid availability (e.g., short-term fasting). The purpose of the present study was to investigate whether the cardiomyocyte circadian clock plays a role in adaptation of the heart to chronic elevations in fatty acid availability. Fatty acid availability was increased in cardiomyocyte-specific CLOCK mutant (CCM) and wild-type (WT) littermate mice for 9 weeks in time-of-day-independent (streptozotocin (STZ) induced diabetes) and dependent (high fat diet meal feeding) manners. Indices of myocardial metabolic adaptation (e.g., substrate reliance perturbations) to STZ-induced diabetes and high fat meal feeding were found to be dependent on genotype. Various transcriptional and post-translational mechanisms were investigated, revealing that Cte1 mRNA induction in the heart during STZ-induced diabetes is attenuated in CCM hearts. At the functional level, time-of-day-dependent high fat meal feeding tended to influence cardiac function to a greater extent in WT versus CCM mice. Collectively, these data suggest that CLOCK (a circadian clock component) is important for metabolic adaption of the heart to prolonged elevations in fatty acid availability.

Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

“…Conversely, inhibition of mTOR via TSC2 results in ablation of the peripheral circadian clock. In fact, mTOR appears to regulate BMAL1 via S6K1 mediated phosphorylation, (118) and control the central circadian clock via regulating the activity of the translational repressor, eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1) (32) Intriguingly, restricting food intake to the active period (for 8 hours, at night time) in mice simultaneously restored circadian variations in TOR activity and prevented the dampening of circadian gene oscillations in mice fed high fat diet, with complete prevention of adverse metabolic consequences (85), and these findings recapitulate independent observations by other groups in murine models with varying dietary composition and timing of feeding (158, 221). Indeed, time-restricted feeding activated circadian cycling of autophagic flux in various tissues (128) and the associated metabolic effects were critically dependent on autophagy.…”

Circadian regulation of metabolic homeostasis: causes and consequences

“…In mice, consumption of a high-fat meal at the end of the active period was associated with increased adiposity, decreased glucose tolerance, hyperinsulinemia, and decreased cardiac function (relative to mice fed the same high-fat meal during the beginning of the active period). 123 , 160 Interestingly, when placed on a high-fat diet in an ad libitum fashion, mice consume an abnormally high proportion of calories during the sleep phase, associated with phase and amplitude effects on peripheral circadian clock gene oscillations, as well as increased adiposity and depressed glucose and insulin tolerance. 62 However, limiting consumption of a high diet only to the active period resulted in improvements in these cardiometabolic parameters (relative to ad libitum high-fat feeding), and increased the amplitude of circadian clock gene expression in multiple metabolically relevant peripheral tissues (eg, liver).…”

NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death

“…NAMPT expression oscillates in a circadian fashion in the heart (Um et al, 2011;Young et al, 2014;Peliciari-Garcia et al, 2016;Li et al, 2020). Previous studies have shown that Nampt gene expression is under the regulation of core clock machineries, circadian locomoter output cycles protein kaput (CLOCK) and brain and muscle Arnt-like protein 1 (BMAL1), as well as SIRT1, which leads to rhythmic cellular NAD + levels (Nakahata et al, 2009;Ramsey et al, 2009;Wijnen, 2009).…”