Evidence for Circadian Control of Endothelial Function in Mice on a High Fat Diet

Abstract

Both human and animal studies demonstrate that a chronic high fat diet (HFD) leads to 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 peripheral molecular clock gene rhythm in mice. However, specific circadian‐dependent mechanisms affecting endothelial function during chronic HFD are poorly understood. Thus, we hypothesized that ad libitum chronic HFD mediates endothelial dysfunction via metabolic arrhythmia and clock gene dysfunction. To test this hypothesis, we designed experiments to measure vascular function in ad libitum and restricted feeding (RF), defined as food availability only during the active phase (ZT 12 to 0 or 7 PM to 7 AM). C57BL/6J 8 week old male mice were provided HFD for 20 weeks ad libitum and separate mice were exposed to RF from weeks 20 to 22 of chronic HFD. Endothelial‐dependent relaxation to acetylcholine in aorta (wire myography) was 1.58 ±0.34 mN in mice provided ad libitum HFD. HFD+RF significantly improved endothelial‐dependent relaxation to 5.12±1.07 mN (n=5–6, p<0.01). In contrast, aortic endothelial‐independent relaxation to the exogenous NO donor, sodium nitroprusside, was similar in ad libitum HFD and HFD+RF mice. In additional experiments, male and female Period2:Luciferase (Per2:Luc) reporter mice were given a normal diet (ND) or HFD for 20 weeks ad libitum and separate groups were subjected to RF from weeks 20 to 22 of ND or HFD. Food consumption and body weight between groups did not differ with 2 weeks of RF. Chronic HFD induced a significantly shortened circadian period of Per2 in aorta (n=4, p=0.0054) compared to ND, and 2 weeks of RF restored the aortic Per2 circadian period in mice on HFD (n=3–4, p=0.0417). Circadian period was unaffected by RF in mice on ND. Interestingly, Per2 rhythm in the perivascular adipose tissue was unaffected by HFD. These findings suggest circadian control of endothelial function during chronic HFD and that HFD induces clock gene arrhythmia specifically disrupting vascular peripheral clocks.Support or Funding InformationThis research was supported by the NIH T32 DK007545 and the UAB School of Medicine AMC21 Multi‐Investigator Grant “Circadian Disruption and Susceptibility to Target Organ Damage.”This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.