Abstract
The mechanisms segregating positive from negative effects of the glucocorticoid receptor (GR) on metabolic health remain poorly elucidated. Here, we generated mice genocopying the human GR polymorphism rs6190, which was sufficient to increase muscle insulin sensitivity and blunt obesity-induced adverse effects on adiposity and exercise intolerance. We identified Foxc1 and Arid5A genes as prospective transactivation targets by the mutant GR in skeletal muscle. In the muscle, we further characterize Foxc1 as transcriptional activator of Insr and Irs1 in the canonical insulin signaling and Arid5a as transcriptional repressor of Cd36 and Fabp4 in the lipid uptake pathway. Moreover, Foxc1 and Arid5a programs in muscle were divergently changed by glucocorticoid regimens with opposite metabolic outcomes. Last, in the UK Biobank and All of Us datasets, the rs6190 variant correlated with prometabolic changes in BMI, lean mass, strength, and glucose control according to zygosity. Collectively, our study leveraged a human nuclear receptor coding variant to unveil epigenetic regulators of muscle metabolism.