The CRISPRa system was utilised in this study to activate the expression and secretion of FGF21 and Irisin, which promotes adipocytes browning in vitro and in vivo, reduces body weight and body fat and improves HFD‐associated WAT hypertrophy, hepatic steatosis, inflammation and fibrosis of DIO mice in vivo. This evidence concerns the gene FNDC5 and fatty liver disease.