Disrupted glucocorticoid rhythms selectively induce severe skeletal muscle insulin resistance and uncouple obesity from hepatic steatosis

Disruption of circadian glucocorticoid (GC) rhythms is associated with chronic stress and obesity, yet its metabolic signature remains poorly defined. Using a physiological mouse model, we show that the liver is largely protected from pathological steatosis despite profound obesity and hyperinsulinemia. We identify a unique redistribution of insulin resistance: rhythm disruption does not globally impair insulin action as occurs in diet-induced obesity. Instead, skeletal muscle develops severe insulin resistance while adipose and hepatic tissues remain functionally insulin responsive. This preserved sensitivity allows the adipose tissue to act as a metabolic reservoir, utilizing sustained hyperinsulinemia to sequester lipids and shield the liver from toxic fatty-acid flux. These findings reveal that GC-rhythm disruption uncouples obesity from hepatic steatosis by redistributing insulin action from skeletal muscle to adipose tissue and liver. Thus, GC-rhythm disruption and high-fat diet are independent and additive drivers of adiposity with divergent hepatic effects.