Agnieszka Agas, Sanjeev Sharma, Anthony Narciso, Lucas Paulo Jacinto Saavedra, Jijo Wilson, Jack Lungstrum, Lucie Yammine, Anna S Arzeno, Louise Lantier, Erin Kilkenny, Ahsan Uddin, Carolina E Echeverria, Katherine R Ferrick, Isaac Nathoo, Jonathan Gao, Edmund D Kapelczak, Rashel Jacobo, Roma Patel, Tara TeSlaa, Marcus D Goncalves, Timothy E McGraw, Mary N Teruel
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.