Glucocorticoid excess induces long-lasting changes in body composition in male C57Bl/6J mice only with high-fat diet.

Glucocorticoid (GC) overexposure period as observed in Cushing's syndrome (CS) is associated with the metabolic syndrome and cardiovascular disease, which persist after long-term correction of GC excess. We performed a mouse study to identify factors that modulate metabolic recovery from a GC overexposure period. Male C57Bl/6J mice, fed a low-fat diet (LFD) or a high-fat diet (HFD), received corticosterone (CORT) (50 µg/mL) or vehicle in the drinking water for 4 weeks, followed by an 8-week washout period. Plasma circadian CORT, lipids, insulin, and glucose levels were assessed regularly. Hyperinsulinemic-euglycemic clamp and body composition were analyzed at week 12 under anesthesia. CORT treatment increased plasma CORT levels, food intake, and plasma insulin and lipid levels on both diets. CORT treatment abrogation normalized CORT levels, food intake, and body weight, whereas plasma insulin levels remained significantly higher in CORT-treated mice on both diets. Only on a HFD, CORT-treated mice had decreased lean body mass and higher fat mass. In conclusion, CORT excess period induces long-lasting metabolic changes and some are present only on a HFD. These observations indicate that diet-dependent CORT effects might contribute to the adverse cardiovascular risk profile observed in CS patients, and possibly also in subjects exposed to chronic stress.

Both transient and continuous corticosterone excess inhibit atherosclerotic plaque formation in APOE*3-leiden.CETP mice.

INTRODUCTION: The role of glucocorticoids in atherosclerosis development is not clearly established. Human studies show a clear association between glucocorticoid excess and cardiovascular disease, whereas most animal models indicate an inhibitory effect of glucocorticoids on atherosclerosis development. These animal models, however, neither reflect long-term glucocorticoid overexposure nor display human-like lipoprotein metabolism. AIM: To investigate the effects of transient and continuous glucocorticoid excess on atherosclerosis development in a mouse model with human-like lipoprotein metabolism upon feeding a Western-type diet. METHODS: Pair-housed female APOE*3-Leiden.CETP (E3L.CETP) mice fed a Western-type containing 0.1% cholesterol for 20 weeks were given corticosterone (50 µg/ml) for either 5 (transient group) or 17 weeks (continuous group), or vehicle (control group) in the drinking water. At the end of the study, atherosclerosis severity, lesion area in the aortic root, the number of monocytes adhering to the endothelial wall and macrophage content of the plaque were measured. RESULTS: Corticosterone treatment increased body weight and food intake for the duration of the treatment and increased gonadal and subcutaneous white adipose tissue weight in transient group by +35% and +31%, and in the continuous group by +140% and 110%. Strikingly, both transient and continuous corticosterone treatment decreased total atherosclerotic lesion area by -39% without lowering plasma cholesterol levels. In addition, there was a decrease of -56% in macrophage content of the plaque with continuous corticosterone treatment, and a similar trend was present with the transient treatment. CONCLUSION: Increased corticosterone exposure in mice with human-like lipoprotein metabolism has beneficial, long-lasting effects on atherosclerosis, but negatively affects body fat distribution by promoting fat accumulation in the long-term. This indicates that the increased atherosclerosis observed in humans in states of glucocorticoid excess may not be related to cortisol per se, but might be the result of complex indirect effects of cortisol.

The effects of high fat diet on the basal activity of the hypothalamus-pituitary-adrenal axis in mice.

Alterations in hypothalamus-pituitary-adrenal (HPA) axis activity have been linked to the development of the metabolic syndrome (MetS). Common features of the MetS, like insulin resistance and obesity, are reproducibly induced by high fat diet (HFD) in animal models of diet-induced obesity. These models, hampered by methodological differences, reveal conflicting results with respect to HPA axis activation. This study was aimed to evaluate in detail nonstressed diurnal HPA axis activity in mice during obesity development. Male C57Bl/6J mice were fed high or low fat diet for 12 weeks. HPA axis activity was evaluated by plasma corticosterone concentrations (at 0700, 1200, and 1800  h), corticotropin-releasing hormone (CRH), and glucocorticoid receptor (GR) mRNA expression in the hippocampus, amygdala, and hypothalamus, and 11ß-hydroxysteroid dehydrogenase type-1 and -2 (11ß-HSD-1 and -2) expression in adipose tissue and liver. Within 1 week, the HFD induced obesity and decreased corticosterone levels at 1200 and 1800  h, which persisted throughout the experiment. Twelve weeks of HFD decreased CRH mRNA in the paraventricular nucleus (PVN) and amygdala and GR mRNA in the PVN at 0900  h. At 1800  h, CRH mRNA expression increased in the PVN and amygdala, and GR mRNA increased in the CA1 region. 11ß-HSD-1 expressions decreased in gonadal, visceral, and subcutaneous adipose tissues at 0900 and 1800  h, whereas hepatic 11ß-HSD-1 expression increased at 1800  h, whereas 11ß-HSD-2 expression was unaffected. The HFD induces complex changes in the diurnal regulation of the different components of the HPA axis. These changes are not unequivocally characterized by increased, but rather by decreased HPA axis activity.