Endocrine and physiological changes in response to chronic corticosterone: a potential model of the metabolic syndrome in mouse

Abstract

Numerous clinical and experimental studies have linked stress to changes in risk factors associated with the development of physiological syndromes, including metabolic disorders. How different mediators of the stress response, such as corticosterone (CORT), influence these changes in risk remains unclear. Although CORT has beneficial short-term effects, long-term CORT exposure can result in damage to the physiological systems it protects acutely. Disruption of this important physiologic signal is observed in numerous disparate disorders, ranging from depression to Cushing's syndrome. Thus, understanding the effects of chronic high CORT on metabolism and physiology is of key importance. We explored the effects of 4-wk exposure to CORT dissolved in the drinking water on the physiology and behavior of male mice. We used this approach as a noninvasive way of altering plasma CORT levels while retaining some integrity in the diurnal rhythm present in normal animals. This approach has advantages over methods involving constant CORT pellets, CORT injections, or adrenalectomy. We found that high doses of CORT (100 microg/ml) result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triglyceride levels, hyperphagia, and decreased home-cage locomotion. A lower dose of CORT (25 microg/ml) resulted in an intermediate phenotype in some of these measures but had no effect on others. We propose that the physiological changes observed in the high-CORT animals approximate changes observed in individuals suffering from the metabolic syndrome, and that they potentially serve as a model for hypercortisolemia and stress-related obesity.

Figure 1

Effects of CORT on body weight and WAT. A, CORT treatment results in rapid weight gain over the 4 wk of treatment in high-CORT (100 μg/ml) animals, but there is no significant effect on low-CORT (25 μg/ml) animals. B, Cumulative weight gain in CORT-treated animals, showing the total weight gain is higher in high-CORT animals when compared with low-CORT or vehicle animals. C, Weight of gonadal WAT is significantly increased after 4 wk of CORT treatment. D, Relative contribution of WAT to total body weight is also significantly increased in high-CORT animals. Asterisks indicate statistical significance at the P < 0.05 level.

Figure 2

Single housing does not affect weight gain due to CORT treatment, and CORT treatment results in hyperphagia. A, Weight change in response to CORT is largely unaffected in single-housed animals, with high-CORT animals still showing a significant weight gain compared with both other treatments. Although low-CORT animals seem to have a slight weight decrease, these differences are not statistically significant. B, Food consumption is altered by CORT treatment, with high-CORT animals showing a significant increase of the amount of food consumed over the 4-wk treatment period. C, High-CORT animals consume more food per gram of body weight per week than either vehicle or low-CORT animals. Asterisks indicate statistical significance at the P < 0.05 level. Bars sharing the same letter are not statistically different from each other.

Figure 3

CORT treatment reduces general home-cage activity. Graph depicts daily home-cage activity as measured by infrared beam breaks in the x, y, and z planes, averaged over four consecutive days. Daytime activity is depressed by high CORT, although not in vehicle or low-CORT animals. At night, activity is significantly attenuated in both the low- and high-CORT animals, with high-CORT animals showing the lowest amount of home-cage activity. Although there were statistically significant differences between daytime and nighttime activity in vehicle and low-CORT animals, this normal diurnal change in the pattern of activity was abolished in high-CORT animals. Bars sharing the same letter are not statistically different from each other.

Figure 4

CORT treatment results in changes in the diurnal pattern of plasma CORT levels. Graph depicts plasma CORT levels taken at the end of the 4-wk treatment, during the light (inactive) or dark (active) phases. Although low-CORT animals had slightly elevated plasma CORT during the dark period (although not statistically significant), high-CORT animals had elevated plasma CORT at both time points, in addition to the light-dark difference. Bars sharing the same letter are not statistically different from each other. Asterisk indicates P = 0.14.

Figure 5

Levels of plasma insulin and plasma leptin are altered by CORT treatment. A and B, Graphs depict changes in plasma insulin (A) and leptin (B) in response to 4 wk of CORT treatment. Both treatments result in elevated plasma levels in both hormones, although levels in high-CORT animals are substantially higher. Bars sharing the same letter are not statistically significant from each other. C and C″, Plots show correlation between an animal’s insulin and leptin levels, as a function of CORT dosage (collapsed across time of day). Although there is no statistically significant correlation of insulin and leptin in vehicle-treated animals, both low- and high-CORT treatment result in statistically significant correlations (P < 0.01), with r² values of 0.65 and 0.89, respectively.

Figure 6

High-CORT treatment results in elevated plasma triglycerides and impaired glucose tolerance. A, Graph depicts plasma triglyceride levels in CORT-treated animals after 4 wk of treatment. High-CORT animals show significantly elevated plasma triglycerides, with over 3-fold higher levels than vehicle-treated animals. Asterisk indicates P < 0.05. B and C, Plasma glucose levels after acute glucose challenge in fasted vehicle or high-CORT mice after either 2 wk (B) or 4 wk (C) of treatment. Although there is no effect of CORT treatment at the 2-wk time point, at the 4-wk time point, high-CORT animals show severely compromised glucose tolerance, with plasma glucose remaining high even 120 min after challenge. Asterisks indicate statistical significance at *, P < 0.05 and **, P < 0.01 levels.