Role of circadian rhythms in chronic high fat diet-induced endothelial dysfunction

Both human and animal studies demonstrate that a chronic high fat diet (HFD) leads to reduced nitric oxide (NO) bioavailability and endothelial dysfunction. Timing of feeding and fasting is known to influence risk for cardiometabolic disease. Ad libitum chronic HFD disrupts the normal circadian rhythm in metabolism and molecular clock gene rhythm in mice. However, specific circadian-dependent mechanisms affecting the endothelium during chronic HFD are poorly understood. The overall goal of this postdoctoral fellowship is to elucidate the relationship(s) of circadian rhythms with chronic HFD-induced endothelial dysfunction. Chronic HFD mediates endothelial dysfunction and vascular disease. Our preliminary studies conducted in mice with 22 weeks of chronic HFD confirmed that chronic HFD abolished aortic endothelial function. Further, our studies with restricting availability of food to the active phase (RF; also increased fasting during the inactive phase) during weeks 20 to 22 of the chronic HFD protocol dramatically restored endothelial function with increased NO bioavailability. These findings suggest that a metabolic rhythm is critical for endothelial function during chronic HFD. Our preliminary studies further show that a chronic HFD in induces aortic circadian clock gene dysfunction. These compelling data led to the hypothesis that ad libitum chronic HFD mediates endothelial dysfunction via aortic metabolic arrhythmia and endothelial clock gene dysfunction. Endothelial function and nitric oxide (NO) production are known to follow a circadian rhythm peaking during the active period. Histone deacetylases (HDACs) play a role in the molecular circadian clock. Our group reported that increased HDAC1 in endothelial cells directly deacetylates NO synthase (NOS3) reducing NO production. Loss of Bmal1, a critical clock gene, results in loss of peak activity during the active phase. Bmal1 knockout mice have endothelial dysfunction with loss of NO bioavailability, suggesting that loss of Bmal1 and circadian rhythms mediates endothelial dysfunction. Preliminary data show that aortic HDAC1 abundance in wild-type mice follows a circadian rhythm, while HDAC1 abundance lacks a rhythm in Bmal1 knockout mice. These data led to the hypothesis that ad libitum chronic HFD leads to endothelial dysfunction via HDAC1 abundance, arrhythmia, and HDAC1-dependent loss of NO bioavailability. (AHA Program: Postdoctoral Fellowship)