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FGF21 regulates metabolism and circadian behavior by acting on the nervous system

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Fibroblast growth factor 21 (FGF21) is a hepatokine that acts as a global starvation signal to modulate fuel partitioning and metabolism and repress growth1; however, the site of action of these diverse effects remains unclear. FGF21 signals through a heteromeric cell-surface receptor composed of one of three FGF receptors (FGFR1c, FGFR2c or FGFR3c) in complex with β-Klotho2,3,4, a single-pass transmembrane protein that is enriched in metabolic tissues5. Here we show that in addition to its known effects on peripheral metabolism, FGF21 increases systemic glucocorticoid levels, suppresses physical activity and alters circadian behavior, which are all features of the adaptive starvation response. These effects are mediated through β-Klotho expression in the suprachiasmatic nucleus of the hypothalamus and the dorsal vagal complex of the hindbrain. Mice lacking the gene encoding β-Klotho (Klb) in these regions are refractory to these effects, as well as those on metabolism, insulin and growth. These findings demonstrate a crucial role for the nervous system in mediating the diverse physiologic and pharmacologic actions of FGF21.

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Figure 1: Klb and Fgfr expression in the nervous system.
Figure 2: Transgenic overexpression of FGF21 alters wheel-running behavior through the SCN.
Figure 3: Endogenous FGF21 alters wheel-running behavior.
Figure 4: Klb expression in the SCN is required for FGF21 suppression of growth and insulin, and stimulation of glucocorticoid activity.

Change history

  • 06 September 2013

     In the version of this article initially published, the color of the key indicating the Klbtm1(Camk2a); Tg(Fgf21) group of mice in Figure 2g was purple when it should have been blue. The error has been corrected in the print, HTML and PDF versions of the article.


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We thank Y. Zhang, K. Vale and E. Borowicz for help with mouse studies, X. Wang and Y. Wan for tibia measurements, D. Lauzon and C. Lee for in situ hybridization, M. Izumo for Camk2a-Cre mice (University of Texas Southwestern Medical Center), M. Scott for Phox2b-Cre mice (University of Virginia), C. Cummins for advice on glucocorticoid and ACTH assays and all members of the Takahashi, Elmquist and Mango/Kliewer laboratories for critical discussions. This work was supported by US National Institutes of Health grants R01DK067158, P20RR20691 and 1RL1GM084436-01 (to S.A.K. and D.J.M.), U19DK62434 (to J.K.E. and D.J.M.), P01DK088761 and RL1DK081185 (to J.K.E.) and GM007062 (to A.L.B.), the Robert A. Welch Foundation (grant I-1558 to S.A.K. and grant I-1275 to D.J.M.) and the Howard Hughes Medical Institute (to J.S.T. and D.J.M.).

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Authors and Affiliations



A.L.B. conceived of the study and, with M.H.M.d.G. designed, performed and analyzed all experiments. B.M.O. designed, performed and analyzed minipump experiments. S.L. and L.G. performed anatomical profiling experiments. H.L.L. generated all study mice and performed experiments. X.D. created the Klbtm1 mouse line. D.J.M., S.A.K., J.S.T. and J.K.E. provided conceptual advice and supervised the project. A.L.B., D.J.M. and S.A.K. wrote the paper.

Corresponding authors

Correspondence to David J Mangelsdorf or Steven A Kliewer.

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Competing interests

D.J.M. has consulted with Novo Nordisk. S.A.K. has consulted with Amgen, Pfizer and Novo Nordisk.

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Supplementary Figures 1–6 and Supplementary Tables 1–4 (PDF 4802 kb)

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Bookout, A., de Groot, M., Owen, B. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 19, 1147–1152 (2013).

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