OR33-04 Mechanistic Dissection Of Circadian-Specific Glucocorticoid Effects On Exercise Tolerance And Muscle Glucose Utilization
Authors: Prabakaran Ashok , Wintzinger Michelle , Piczer Kevin , Miz Karen , Walton Alicia , Bindu Durumutla Hima , Quattrocelli Mattia 
Published: October 2023

Disclosure: A. Prabakaran: None. M. Wintzinger: None. K. Piczer: None. K. Miz: None. A. Walton: None. H. Durumutla: None. M. Quattrocelli: None.

Glucocorticoids (GCs) are circadian hormones regulating metabolism by activating the glucocorticoid receptor (GR) as pleiotropic transcription factor. Timing of exogenous GC drug regimens is emerging as a key determinant of their metabolic effects. This was shown by the surprising finding that once-weekly GC intermittence reverses many of the pro-obesogenic side effects of once-daily GC dosing in mice and humans. However, despite the intrinsic circadian nature of this signaling, the impact of time-of-day of exogenous GC dosing, i.e. chrono-pharmacology, remains remarkably unknown for metabolic physiology and exercise tolerance. Relevance of this question for humans is supported by the initial findings of increased lean mass and motor function with circadian-restricted prednisone intermittence in a recent pilot clinical trial in patients with genetic myopathies. However, mechanisms to support significance of these effects for metabolic diseases and aging remain unknown. We studied 12-week-long intermittent regimens of the exogenous GC prednisone in mice in conditions of diet-induced obesity or advanced aging, comparing dosing at light-phase start (ZT0) versus dark-phase start (ZT12). We found that, compared to dark-phase, light-phase dosing enhanced the regimen-driven increase in body-wide lean mass, muscle mass and muscle function in both obese and aged mice. Intriguingly, experiments with adiponectin-knockout mice showed that these effects were dependent on adiponectin, which promotes muscle insulin sensitivity. We then used tissue-specific inducible knockout models to dissect non-muscle versus muscle-autonomous effects of GC chrono-pharmacology. We found that the GC effects on total and high-molecular-weight adiponectin upregulation were dependent on regimen-specific engagement of the adipocyte-specific GR on the adiponectin gene promoter. Complementary to adipose-driven adiponectin production, we found that adiponectin receptor AdipoR1 upregulation in muscle depended on circadian-specific engagement of the myocyte-specific GR on the AdipoR1 promoter. Consistent with the adiponectin action on muscle insulin sensitivity, ablation of myocyte-specific GR blocked the regimen-driven effects on insulin-sensitive muscle glucose uptake and muscle mass. Furthermore, we found that light-phase GC dosing engaged the muscle GR for a non-canonical interaction with the clock factor BMAL1 to upregulate the mitochondrial regulator PGC1alpha. Indeed, we found that the regimen-driven increase in glucose oxidation and amino acid biogenesis from TCA cycle intermediates in muscle was dependent on the myocyte-specific PGC1alpha. In summary, we present here novel circadian and molecular mechanisms reconverting glucocorticoid drugs from deleterious to re-energizing agents for potential chrono-treatment of metabolic conditions and aging.

Presentation: Sunday, June 18, 2023