Effects of high fat diet and chronic circadian challenge on glucocorticoid regulation in C57BL/6J mice

Both high-fat diet and chronic circadian disruption have been associated with increased incidence of obesity and type 2 diabetes in humans. Chronically elevated glucocorticoids, which have considerable impacts on physiological processes such as intermediary metabolism, inflammation, and fat metabolism, have also been implicated in insulin resistance associated with obesity and diabetes. In this study, the effects of high-fat diet (HFD) or chronic circadian challenge in C57BL/6J mice on basal and stress-induced corticosterone (CORT) and blood glucose levels were assessed. Baseline and stress-induced levels of CORT, insulin and glucose were measured before and after acute restraint stress at 4 different time points across the light-dark cycle (LD) in male C57BL/6J mice maintained for 8 weeks on HFD or regular chow. After 8 weeks on diet, baseline CORT levels in HFD mice were of similar magnitude but more variable than in mice on low-fat diet, rendering their daily fluctuations arrhythmic according to statistical analysis. Baseline glucose measures were unchanged despite significant 3-fold increases in baseline insulin levels in HFD mice at all time points sampled. Restraint stress yielded considerable decreases in insulin levels and increases in CORT and glucose levels that were significantly exaggerated in the early active period in mice on HFD. These results indicate a circadian influence on stress responses after prolonged consumption of high fat diet. In a separate experiment, C57BL/6J mice were subjected to 6 weeks of an alternating light-dark (LD) cycle comprised of 6 h advances and delays of phase every 5 days to keep the circadian system from establishing consistent circadian entrainment, with a control group of mice under a regular 12:12 LD cycle. While body weights were not significantly affected by chronic circadian challenge, the basal CORT rhythm in alternating-LD mice was significantly dampened. Stress-induced CORT in alternating ID were no different from regular ID group with the exception of ZT 18, at which time the stress response was moderately suppressed compared to controls. These results support that high-fat diet may be contributing to health disorders such as obesity and diabetes in a manner different from any effects of chronic circadian disruption.