FASEB J. 2022 May;36 Suppl 1
Circadian rhythm disruption increases cardiometabolic disease risk. For example, night shift workers have an increased risk of developing metabolic syndrome, hypertension, and endothelial dysfunction. Loss of Bmal1, an essential circadian clock gene, impairs cardiometabolic rhythms and promotes endothelial dysfunction. We hypothesized that chronic light cycle disruption increases fat mass, blunts metabolic rhythms, and leads to cardiovascular disease in adult mice dependent on the molecular circadian clock. Littermate wild type (WT) and global Bmal1-KO mice (5-7 month old males) were maintained on a standard light/dark cycle (control, 12-h light, 12-h dark) or a chronic circadian disruption protocol (CCD,10-h light, 10-h dark for 14-18 weeks) with food and water available ad libitum. Food intake over 24-h was similar between all groups. Body weight was similar between WT control and WT CCD mice whereas weight was lower in Bmal1-KO mice with control and CCD conditions (p<0.01 WT vs Bmal1-KO, n=3-4). Body composition measured by quantitative magnetic resonance revealed lower fat mass in Bmal1-KO control as well as both WT CCD and Bmal1-KO CCD mice compared to WT on the control schedule (p<0.01 WT control vs WT CCD; p=0.02 WT vs Bmal1-KO; n=3-4). Lean mass was not different between control and CCD WT mice but was lower in Bmal1-KO mice regardless of light cycle (p<0.01 WT vs Bmal1-KO; n=3-4). Total body water was similar in control and CCD WT mice but significantly lower in both control and CCD Bmal1-KO mice (p<0.01 WT vs Bmal1-KO; n=3-4). Respiratory exchange ratio measured by indirect calorimetry during light and dark phases was not significantly different between groups although both groups of KO mice were significantly higher than controls (p=0.04; n=3-4). As expected, there was a light-dark phase difference in energy expenditure (EE) in WT control mice, whereas the light-dark phase difference in EE was absent in WT CCD mice (p=0.05 WT control dark vs light; p>0.05 WT CCD dark vs. light; n=3-4). Bmal1-KO control mice lacked a light-dark phase difference in EE. CCD did not affect the EE light-dark phase difference in Bmal1-KO mice. Aortic stiffness, measured by pulse wave velocity, was similar in WT under control and CCD and in Bmal1-KO mice in both conditions (p>0.05). Systolic blood pressure (tail-cuff) was similar in WT control and CCD mice, yet lower in both control and CCD Bmal1-KO mice (p=0.02 WT control vs Bmal1-KO; p=0.04 WT CCD vs Bmal1-KO CCD; n=4-5). In isolated vessels, aortic endothelial-dependent relaxation was not impaired by CCD in WT mice but attenuated in both control and CCD Bmal1-KO mice (p<0.01; n=4-5). Endothelial-independent relaxation was similar between all groups. In conclusion, we found that CCD decreases fat mass in older adult WT mice and dampens EE rhythm, while Bmal1-KO mice have reduced fat and lean mass, total water, and blunted EE rhythm regardless of light cycle. These data suggest that metabolic changes due to light cycle disruption may be dependent on the molecular clock.