Here, we demonstrate for the first time that a single administration of AAV vectors encoding FGF21 enabled a long‐lasting increase in FGF21 levels in circulation, which resulted in sustained counteraction of obesity, hepatic steatosis, and insulin resistance in two different models of obesity and T2D, the HFD‐fed mouse and the ob/ob mouse. The gene discussed is FGF21; the disease is Hepatic steatosis.