Severe caloric restriction, in a setting of regular physical exercise, may be a stress that sets the stage for adiposity rebound and insulin resistance when the food restriction and exercise stops. In this study, we examined the effect of mifepristone, a glucocorticoid (GC) receptor antagonist, on limiting adipose tissue mass gain and preserving whole-body insulin sensitivity following the cessation of daily running and caloric restriction (CR). We calorically restricted male Sprague-Dawley rats and provided access to voluntary running wheels for three weeks followed by locking of the wheels and reintroduction to ad libitum feeding with or without mifepristone (80 mg/kg/day) for one week. Cessation of daily running and CR increased HOMA-IR, visceral adipose mass as well as glucose and insulin area under the curve during an oral glucose tolerance test versus pre-wheel lock exercised rats and sedentary rats (all p<0.05). Insulin sensitivity and glucose tolerance were preserved and adipose tissue mass gain was attenuated by daily mifepristone treatment during the post-wheel lock period. These findings suggest that following regular exercise and CR there are GC-induced mechanisms that promote adipose tissue mass gain and impaired metabolic control in healthy organisms and that this phenomenon can be inhibited by the GC receptor antagonist mifepristone.