Conversion of a paracrine fibroblast growth factor into an endocrine fibroblast growth factor

FGFs 19, 21, and 23 are hormones that regulate in a Klothoco-receptor- dependent fashion major metabolic processes suchas glucose and lipid metabolism (FGF21) and phosphate andvitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycanin the formation of the cell surface signalingcomplex of endocrine FGFs has remained unclear. Here we showthat heparan sulfate is not a component of the signal transductionunit of FGF19 and FGF23. In support of our model, weconvert a paracrine FGF into an endocrine ligand by diminishingheparan sulfate-binding affinity of the paracrine FGF andsubstituting its C-terminal tail for that of an endocrine FGF containingthe Klotho co-receptor-binding site to home the ligandinto the target tissue. In addition to serving as a proof of concept,the ligand conversion provides a novel strategy for engineeringendocrine FGF-like molecules for the treatment of metabolicdisorders, including global epidemics such as type 2 diabetesand obesity.