Adiponectin is the most abundant adipokine in our circulation and regulates inter-tissue communication like the adipose-muscle axis. Pharmacological modulation of this crosstalk is beneficial in promoting exercise tolerance in metabolic stress conditions like obesity. Endogenous glucocorticoids regulate metabolic function and stress response, but chronic daily intake of exogenous glucocorticoids produces or exacerbates metabolic stress. However, in stark contrast to daily intake, we discovered that intermittent regimens of glucocorticoids, e.g. once-weekly, improves exercise tolerance. However, the mechanisms underlying the differential regimen-specific effects of glucocorticoids in obesity remain unknown. Here we investigated the mechanisms differentiating once-weekly versus once-daily regimens of the same glucocorticoid prednisone in obesity. In mice with diet-induced obesity, once-weekly prednisone stimulated total and high-molecular weight adiponectin levels, improving exercise tolerance and energy expenditure. These effects were dependent upon adiponectin and were blocked by genetic ablation of the adipokine. Upregulation of Adipoq occurred through the adipose-specific glucocorticoid receptor (GR) , as this effect was blocked in mice with inducible GR ablation in adipose tissue. In contrast, once-daily prednisone decreased adiponectin levels through upregulation of known repressors of adiponectin expression in adipose tissue. The drug regimens remodeled in opposite ways also transcriptome and function in skeletal muscle after onset of obesity. Particularly, once-weekly prednisone treatment increased the muscle metabolic response to adiponectin through the CAMKK2-AMPK cascade. Our study demonstrates that intermittent glucocorticoids produce healthful metabolic remodeling in diet-induced obesity through direct upregulation of adiponectin expression in adipose tissue and adiponectin-dependent signaling in skeletal muscle.
M.Wintzinger: Employee; Cincinnati Children's Hospital. K.Miz: None. M.Panta: None. H.Durumutla: None. A.Pragasam: None. M.Quattrocelli: None.
National Institutes of Health grant DK121875National Institutes of Health grant HL158531CCHMC Trustee AwardCCHMC Heart Institute Translational Grant