BetaKlotho is required for metabolic activity of fibroblast growth factor 21

Proc Natl Acad Sci U S A. 2007 May 1;104(18):7432-7. doi: 10.1073/pnas.0701600104. Epub 2007 Apr 23.


Fibroblast growth factor 21 (FGF21) is a liver-derived endocrine factor that stimulates glucose uptake in adipocytes. Here, we show that FGF21 activity depends on betaKlotho, a single-pass transmembrane protein whose expression is induced during differentiation from preadipocytes to adipocytes. BetaKlotho physically interacts with FGF receptors 1c and 4, thereby increasing the ability of these FGF receptors to bind FGF21 and activate the MAP kinase cascade. Knockdown of betaKlotho expression by siRNA in adipocytes diminishes glucose uptake induced by FGF21. Importantly, administration of FGF21 into mice induces MAP kinase phosphorylation in white adipose tissue and not in tissues without betaKlotho expression. Thus, betaKlotho functions as a cofactor essential for FGF21 activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Animals
  • Cell Line
  • Fibroblast Growth Factors / metabolism*
  • Gene Expression Regulation
  • Humans
  • Membrane Proteins / classification
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Protein Binding
  • Receptors, Fibroblast Growth Factor / metabolism
  • Signal Transduction


  • Klb protein, mouse
  • Membrane Proteins
  • Receptors, Fibroblast Growth Factor
  • fibroblast growth factor 21
  • Fibroblast Growth Factors