FGFs however, cannot interact directly with their respective receptors but instead requires a co-factor spe cifcally β-Klotho, from the Klotho-family to profciently bind and activate FGFR signaling. Myriads of studies proposed and confrmed that the c-receptor splice isoforms of FGFR1–3 exhibits a particular afnity to β-Klotho and thus act as endogenous receptors required for the function of FGF21 .