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. This evidence concerns the gene FGF21 and obesity due to melanocortin 4 receptor deficiency.