Differential effects of high-fat diet on glucose tolerance, food intake, and glucocorticoid regulation in male C57BL/6J and BALB/cJ mice.

The C57BL/6J strain of laboratory mice is a popular subject for studies of diet-induced obesity and diabetes given its propensity for developing obesity and glucose intolerance when placed on high-fat diet. High-fat diet leads to much lower weight gain in young adult BALB/cJ mice, which appear to be protected from many of the metabolic effects of high-fat diet observed in C57BL/6J mice. In this report, the effects of diet and timing of feeding on body weight, food intake, glucose tolerance, and stress-induced corticosterone and blood glucose responses were assessed in male C57BL/6J and BALB/cJ mice. Lower glucose tolerance was observed in low-fat diet-fed C57BL/6J than BALB/cJ mice at four times sampled across the circadian cycle. Ad libitum high-fat diet increased the amount of daytime eating behavior and led to impaired glucose regulation in C57BL/6J but not BALB/cJ mice. Restricting food availability to either daytime or nighttime did not prevent overall body weight gain, but restricting feeding to nighttime (but not daytime) did prevent the significant increase in perigonadal fat pad mass produced by high-fat diet in C57BL/6J mice. Baseline corticosterone levels at their typical daily peak near onset of daily activity were blunted in both strains of mice after 8 weeks on high-fat diet, without corresponding differences in baseline glucose levels. Restraint stress-induced increases in corticosterone were exaggerated in C57BL/6J mice on high-fat diet, with concomitant increases in blood glucose. Paradoxically, stress-induced corticosterone responses were even more exaggerated in BALB/cJ mice yet with significantly blunted glucose responses compared to C57BL/6J mice, regardless of diet, indicating that corticosterone does not have equivalent glucogenic effects in young adult male BALB/cJ and C57BL/6J mice on high-fat diet. These results document considerable strain differences that may provide means for elucidating the mechanisms involved in diet-induced obesity, while highlighting the need to consider these strain differences when extending the results of mouse studies toward the human condition.

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 LD were no different from regular LD 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.