The cessation of regular exercise and dieting causes rapid adiposity rebound and glucose intolerance in young male rats, findings that are abolished by the glucocorticoid receptor antagonist Mifepristone (LB759)

Abstract

A rapid deterioration of whole‐body insulin sensitivity and visceral fat mass rebound occurs following cessation of regular exercise in humans and rodents. Both dieting and daily exercise have been shown to increase intracellular visceral fat exposure to glucocorticoids (GCs) via up‐regulation of the pre‐receptor enzyme 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1), a phenomenon that may predispose animals to rapid fat rebound. We hypothesized that sustained elevations of GC exposure in visceral fat, upon removal of regular exercise and caloric restriction (CR), may influence this detrimental metabolic response. Thus, we tested the efficacy of Mifepristone, a potent but non‐selective GC receptor antagonist, on limiting adiposity rebound and preserving whole‐body insulin sensitivity following cessation of daily exercise and CR. Using young male Sprague‐Dawley rats, we provided 20g/day of standard rodent chow and access to voluntary running wheels for 3 weeks followed by locking of the wheels and reintroduction to ad libitum feeding either with or without Mifepristone (80 mg/kg/day) via oral gavage for 1 week. Additional Sedentary and Control Runner groups, who were also calorie restricted (20 g/day), were used as pre‐wheel lock comparisons (n= 8‐10 per group). Cessation of daily running and CR resulted in a 6.5‐fold increase in HOMA‐IR and a 2‐fold increase in glucose AUC during an oral glucose tolerance test in Placebo vs. Control Runners (p<0.05). Mifepristone treatment abolished both of these impairments. Mifepristone also attenuated visceral fat mass rebound in epididymal depots by 14% vs. Placebo and significantly reduced perirenal fat mass rebound by 55% vs. Placebo (p<0.05). Control Runners demonstrated a 5‐fold increase in 11β‐HSD1 protein content in epididymal fat vs. Sedentary and a similar increase remained in the Placebo group one week following cessation of exercise and CR vs. Sedentary (p<0.05). Daily Mifepristone significantly reduced 11β‐HSD1 vs. Control Runners and Placebo groups (p<0.05). These findings suggest that elevations in GC action following regular exercise and dieting promote rapid deterioration in metabolic control in healthy organisms and that this deterioration can be inhibited by a GC receptor antagonist. Grant Funding Source: Supported by NSERC and Corcept Therapeutics