Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction

Abstract

Teich T, Dunford EC, Porras DP, Pivovarov JA, Beaudry JL, Hunt H, Belanoff JK, Riddell MC. Glucocorticoid antagonism limits adiposity rebound and glucose intolerance in young male rats following the cessation of daily exercise and caloric restriction. Am J Physiol Endocrinol Metab 311: E56 -E68, 2016. First published May 3, 2016 doi:10.1152/ajpendo.00490.2015.-Severe caloric restriction (CR), 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 stop. 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 CR. We calorically restricted male Sprague-Dawley rats and provided access to voluntary running wheels for 3 wk followed by locking of the wheels and reintroduction to ad libitum feeding with or without mifepristone (80 mg·kg Ϫ1 ·day Ϫ1 ) for 1 wk. Cessation of daily running and CR increased HOMA-IR and visceral adipose mass as well as glucose and insulin area under the curve during an oral glucose tolerance test vs. pre-wheel lock exercised rats and sedentary rats (all P Ͻ 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. exercise; caloric restriction; glucocorticoid antagonism; glucose intolerance; adiposity rebound REPEATED BOUTS OF WEIGHT LOSS and weight regain, termed weight cycling, have been associated with a greater risk for developing cardiovascular disease and type 2 diabetes over time (5,20,26). Although caloric restriction (CR) and regular exercise reduce body fat content and improve metabolic health (74), a key component to their success is adherence. Following weight loss from CR in overweight or obese individuals, nearly one-half of the weight is regained within one year (16). This weight regain is associated with a marked deterioration in whole body insulin sensitivity, which may occur via increased adipose tissue hypertrophy and hyperplasia, changes in neuroendocrine inputs to adipose tissue (43), and reductions in skeletal muscle insulin sensitivity (32). Although regular exercise attenuates the metabolic drive to regain weight after long-term weight loss in animal models (44), humans tend to relapse toward more sedentary behavior after lifestyle interventions (79). Humans (1, 25, 31, 52, 57, 73) and rodents (13, 32-34, 36, 37) rapidly develop significant insulin resistance, glucose intolerance, and visceral fat growth when increased physical activity or dieting stops. Additionally, the reintroduction to ad libitum feeding followi...

Transition from physical activity to inactivity increases skeletal muscle miR-148b content and triggers insulin resistance

“…The specific protocol conditions (mild intensity of the changes may explain the lack of change for miR-133a that had been observed in more severe conditions as bed rest (Ringholm et al 2011a) or acute exercise (Russell et al 2013)). Rodent wheel-lock protocols have been used to demonstrate insulin sensitivity reduction at both muscle (Kump and Booth 2005) and whole body levels (Teich et al 2016). Our data in mice are in agreement with previous studies showing that muscle disuse also lead to an increase in miR-148b level in rats soleus muscle after 7 days of hind-limb suspension (McCarthy et al 2009).…”

“…Rodent wheel‐lock protocols have been used to demonstrate insulin sensitivity reduction at both muscle (Kump and Booth ) and whole body levels (Teich et al. ). Our data in mice are in agreement with previous studies showing that muscle disuse also lead to an increase in miR‐148b level in rats soleus muscle after 7 days of hind‐limb suspension (McCarthy et al.…”

Adiposity rebound from three to six years of age was associated with a higher insulin resistance risk at eight‐and‐a‐half years in a birth cohort study

“…Early adiposity rebound under the age of five was significantly associated with HOMA-IR and adverse metabolic scores. Fat deposition and impaired metabolic control is probably mediated through the glucocorticoid pathway, as the glucocorticoid receptor antagonist has been shown to inhibit this phenomenon in mice (24). Our findings add further information, by pointing out that the critical period is three to six years.…”

“…Excess fat is retained and tracks into adulthood, leading to obesity and its cardiometabolic consequences later in life (7,22). Fat deposition and impaired metabolic control is probably mediated through the glucocorticoid pathway, as the glucocorticoid receptor antagonist has been shown to inhibit this phenomenon in mice (24).…”

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Development by Lentiviral Screening Based on Computational Modeling

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