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Selective activation of FGFR4 by an FGF19 variant does not improve glucose metabolism in ob/ob mice

Xinle Wu1, Hongfei Ge, Bryan Lemon

  • 1Amgen Inc, South San Francisco, CA 94080, USA. xinlew@amgen.com

Proceedings of the National Academy of Sciences of the United States of America
|August 27, 2009
PubMed

Insights

Fibroblast Growth Factor 19 (FGF19) interactions with its receptors are complex. A modified FGF19 (FGF19dCTD) specifically activates FGFR4, impacting liver bile acid regulation but not glucose homeostasis.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Fibroblast Growth Factor 19 (FGF19) is a hormone crucial for bile acid and glucose homeostasis.
  • Understanding FGF19's receptor specificity and cofactor requirements, like betaKlotho and heparin, is essential for defining its functions.
  • Previous research highlighted progress in identifying cofactors but left several FGF19 actions undefined.

Purpose of the Study:

  • To investigate the specific requirements for FGF19-Fibroblast Growth Factor Receptor (FGFR) interactions and signaling.
  • To elucidate the roles of betaKlotho and heparin in mediating FGF19's effects on different FGFRs.
  • To develop and characterize a novel FGF19 variant (FGF19dCTD) with specific FGFR4 activation properties.

Main Methods:

  • Investigated FGF19 binding and signaling across various FGFRs (FGFR1c, FGFR2c, FGFR3c, FGFR4) in the presence and absence of betaKlotho and heparin.
  • Generated a modified FGF19 molecule, FGF19dCTD, by deleting the C-terminal domain responsible for betaKlotho interaction.
  • Administered FGF19 and FGF19dCTD to ob/ob mice to assess in vivo effects on liver gene expression (CYP7A1), glucose levels, and insulin sensitivity.

Main Results:

  • BetaKlotho is essential for FGF19 interaction with FGFR1c, FGFR2c, and FGFR3c, but not for FGFR4 interaction, which is heparin-dependent.
  • FGF19 activates FGFR4 signaling with or without betaKlotho, while FGFR1c, FGFR2c, and FGFR3c activation is strictly betaKlotho-dependent.
  • FGF19dCTD selectively activated FGFR4 signaling in the liver, suppressed CYP7A1 expression, but did not improve glucose levels or insulin sensitivity in mice, unlike native FGF19.

Conclusions:

  • FGF19's regulation of liver bile acid metabolism may be independent of its glucose-lowering effects.
  • Direct FGFR4 activation in adipose tissue might be critical for glucose homeostasis, suggesting distinct roles for FGF19 signaling pathways.
  • FGF19dCTD serves as a valuable tool for dissecting FGF19 signaling pathways, particularly highlighting the specific role of FGFR4 in hepatic functions.

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