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. e00103 Clinical data indicate that a period of cortisol overexposure, as observed in Cushing's syndrome, leads to irreversible metabolic changes. In the current study, we demonstrate, for the first time, that a period of increased corticosterone levels in mice induces persistent abnormalities in body composition (decreased lean body mass and higher fat mass), despite normalization of food intake and body weight, only on a high‐fat diet. These observations indicate that diet‐dependent corticosterone effects might contribute to the adverse cardiovascular risk profile observed in Cushing's syndrome patients, and possibly also in subjects exposed to chronic stress.