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. The gene discussed is FGF21; the disease is fatty liver disease.