The metabolic consequences of chronic AMPK activation exhibited by MKRN1-null mice led us to investigate whether hepatic AMPK activation was sufficient to improve NAFLD without affecting the activation of AMPK in adipose tissue and whether the acute reduction of MKRN1 expression would alleviate the symptoms of hepatic steatosis in obese mice. Here, MKRN1 is linked to metabolic dysfunction-associated steatotic liver disease.