Taken together, our data provide a novel mechanistic understanding of the biological functions of FGF21 on vascular diseases challenged with metabolic disorders and demonstrate that FGF21 is a potent and effective protein to treat endothelial dysfunction through the direct suppression of oxidative stress and enhancement of eNOS signaling via CaMKK2/AMPKα activation in diabetes (Fig. 8). Here, FGF21 is linked to endothelial dysfunction.