βKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c

Fibroblast growth factor (FGF) 21, a structural relative of FGF23 that regulates phosphate homeostasis, is a regulator of insulin-independent glucose transport in adipocytes and plays a role in the regulation of body weight. It also regulates ketogenesis and adaptive responses to starvation. We report that in a reconstituted receptor activation assay system using BaF3 cells, which do not endogenously express any type of FGF receptor ( FGFR) or heparan sulfate proteoglycan, FGF21 alone does not activate FGFRs and that beta Klotho is required for FGF21 to activate two specific FGFR subtypes: FGFR1c and FGFR3c. Coexpression of beta Klotho and FGFR1c on BaF3 cells enabled FGF21, but not FGF23, to activate receptor signaling. Conversely, coexpression of FGFR1c and Klotho, a protein related to beta Klotho, enabled FGF23 but not FGF21 to activate receptor signaling, indicating that expression of beta Klotho/ Klotho confers target cell specificity on FGF21/FGF23. In all of these cases, heparin enhanced the activation but was not essential. In 3T3-L1 adipocytes, up-regulation of glucose transporter ( GLUT) expression by FGF21 was associated with expression of beta Klotho, which was absent in undifferentiated 3T3-L1 fibroblasts. It is thus suggested that beta Klotho expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion.