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PNAS 104 (18): 7432-7437

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

betaKlotho is required for metabolic activity of fibroblast growth factor 21

Yasushi Ogawa*, Hiroshi Kurosu*, Masaya Yamamoto*, Animesh Nandi*, Kevin P. Rosenblatt*, Regina Goetz{dagger}, Anna V. Eliseenkova{dagger}, Moosa Mohammadi{dagger}, and Makoto Kuro-o*,{ddagger}

*Department of Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390; and {dagger}Department of Pharmacology, New York University School of Medicine, 550 First Avenue, MSB 425, New York, NY 10016

Edited by Michael S. Brown, University of Texas Southwestern Medical Center, Dallas, TX, and approved March 26, 2007

Received for publication February 21, 2007.

Abstract: 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.

Key Words: Klotho • glucose • adipocyte • siRNA • GLUT1

Freely available online through the PNAS open access option.

Author contributions: Y.O. and H.K. contributed equally to this work; Y.O., H.K., and M.K. designed research; Y.O, H.K., M.Y., A.N., and M.K. performed research; A.N., K.P.R., R.G., A.V.E., and M.M. contributed new reagents/analytic tools; Y.O., H.K., and M.K. analyzed data; and Y.O., H.K., M.M. and M.K. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

{ddagger}To whom correspondence should be addressed. E-mail: makoto.kuro-o{at}utsouthwestern.edu

© 2007 by The National Academy of Sciences of the USA

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