Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature Medicine volume 19, pages 1147–1152 (2013)Cite this article

Subjects

This article has been updated

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Potthoff, M.J., Kliewer, S.A. & Mangelsdorf, D.J. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 26, 312–324 (2012).

    Article  CAS  Google Scholar 

  2. Kharitonenkov, A. et al. FGF-21/FGF-21 receptor interaction and activation is determined by β-Klotho. J. Cell Physiol. 215, 1–7 (2008).

    Article  CAS  Google Scholar 

  3. Ogawa, Y. et al. β-Klotho is required for metabolic activity of fibroblast growth factor 21. Proc. Natl. Acad. Sci. USA 104, 7432–7437 (2007).

    Article  CAS  Google Scholar 

  4. Suzuki, M. et al. β-Klotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c. Mol. Endocrinol. 22, 1006–1014 (2008).

    Article  CAS  Google Scholar 

  5. Fon Tacer, K. et al. Research resource: comprehensive expression atlas of the fibroblast growth factor system in adult mouse. Mol. Endocrinol. 24, 2050–2064 (2010).

    Article  Google Scholar 

  6. Hsuchou, H., Pan, W. & Kastin, A.J. The fasting polypeptide FGF21 can enter brain from blood. Peptides 28, 2382–2386 (2007).

    Article  CAS  Google Scholar 

  7. Tan, B.K. et al. Fibroblast growth factor 21 (FGF21) in human cerebrospinal fluid: relationship with plasma FGF21 and body adiposity. Diabetes 60, 2758–2762 (2011).

    Article  CAS  Google Scholar 

  8. Yang, C. et al. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS ONE 7, e33870 (2012).

    Article  CAS  Google Scholar 

  9. Coskun, T. et al. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 149, 6018–6027 (2008).

    Article  CAS  Google Scholar 

  10. Sarruf, D.A. et al. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 59, 1817–1824 (2010).

    Article  CAS  Google Scholar 

  11. Dibner, C., Schibler, U. & Albrecht, U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu. Rev. Physiol. 72, 517–549 (2010).

    Article  CAS  Google Scholar 

  12. Huang, W., Ramsey, K.M., Marcheva, B. & Bass, J. Circadian rhythms, sleep, and metabolism. J. Clin. Invest. 121, 2133–2141 (2011).

    Article  CAS  Google Scholar 

  13. Buijs, R.M. & Kalsbeek, A. Hypothalamic integration of central and peripheral clocks. Nat. Rev. Neurosci. 2, 521–526 (2001).

    Article  CAS  Google Scholar 

  14. Welsh, D.K., Takahashi, J.S. & Kay, S.A. Suprachiasmatic nucleus: cell autonomy and network properties. Annu. Rev. Physiol. 72, 551–577 (2010).

    Article  CAS  Google Scholar 

  15. Lowey, A.D. & Spyer, M. Central Regulation of Autonomic Functions. (Oxford University Press, New York, 1990).

  16. Inagaki, T. et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 5, 415–425 (2007).

    Article  CAS  Google Scholar 

  17. Ding, X. et al. β-Klotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab. 16, 387–393 (2012).

    Article  CAS  Google Scholar 

  18. Casanova, E. et al. A CamKIIα iCre BAC allows brain-specific gene inactivation. Genesis 31, 37–42 (2001).

    Article  CAS  Google Scholar 

  19. Scott, M.M., Williams, K.W., Rossi, J., Lee, C.E. & Elmquist, J.K. Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice. J. Clin. Invest. 121, 2413–2421 (2011).

    Article  CAS  Google Scholar 

  20. Badman, M.K., Koester, A., Flier, J.S., Kharitonenkov, A. & Maratos-Flier, E. Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 150, 4931–4940 (2009).

    Article  CAS  Google Scholar 

  21. Inagaki, T. et al. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab. 8, 77–83 (2008).

    Article  CAS  Google Scholar 

  22. Buijs, R.M., Kalsbeek, A., van der Woude, T.P., van Heerikhuize, J.J. & Shinn, S. Suprachiasmatic nucleus lesion increases corticosterone secretion. Am. J. Physiol. 264, R1186–R1192 (1993).

    CAS  PubMed  Google Scholar 

  23. Ritter, S., Dinh, T.T. & Zhang, Y. Localization of hindbrain glucoreceptive sites controlling food intake and blood glucose. Brain Res. 856, 37–47 (2000).

    Article  CAS  Google Scholar 

  24. Cahill, G.F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22 (2006).

    Article  CAS  Google Scholar 

  25. Wang, T., Hung, C.C. & Randall, D.J. The comparative physiology of food deprivation: from feast to famine. Annu. Rev. Physiol. 68, 223–251 (2006).

    Article  Google Scholar 

  26. Potthoff, M.J. et al. FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc. Natl. Acad. Sci. USA 106, 10853–10858 (2009).

    Article  CAS  Google Scholar 

  27. Owen, B.M. et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat. Med. advance online publication, 10.1038/nm.3250 (11 August 2013).

  28. Hâkansson, M.L., Brown, H., Ghilardi, N., Skoda, R.C. & Meister, B. Leptin receptor immunoreactivity in chemically defined target neurons of the hypothalamus. J. Neurosci. 18, 559–572 (1998).

    Article  Google Scholar 

  29. Zigman, J.M., Jones, J.E., Lee, C.E., Saper, C.B. & Elmquist, J.K. Expression of ghrelin receptor mRNA in the rat and the mouse brain. J. Comp. Neurol. 494, 528–548 (2006).

    Article  CAS  Google Scholar 

  30. Woo, Y.C., Xu, A., Wang, Y. & Lam, K.S.L. Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin. Endocrinol. (Oxf) 78, 489–496 (2013).

    Article  CAS  Google Scholar 

  31. Paxinos, G. & Franklin, K.B.J. The Mouse Brain in Stereotaxic Coordinates. 1–456 (Academic Press, San Diego, 2003).

  32. Lee, S. et al. Laser-capture microdissection and transcriptional profiling of the dorsomedial nucleus of the hypothalamus. J. Comp. Neurol. 520, 3617–3632 (2012).

    Article  CAS  Google Scholar 

  33. Bookout, A.L., Cummins, C.L., Mangelsdorf, D.J., Pesola, J.M. & Kramer, M.F. High-throughput real-time quantitative reverse transcription PCR. Curr. Protocol. Mol. Bio. Unit 15.8 (2006).

  34. Cummins, C.L. et al. Liver X receptors regulate adrenal cholesterol balance. J. Clin. Invest. 116, 1902–1912 (2006).

    Article  CAS  Google Scholar 

  35. Siepka, S.M. & Takahashi, J.S. Methods to record circadian rhythm wheel running activity in mice. Methods Enzymol. 393, 230–239 (2005).

    Article  CAS  Google Scholar 

  36. Shimomura, K. et al. Genome-wide epistatic interaction analysis reveals complex genetic determinants of circadian behavior in mice. Genome Res. 11, 959–980 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.).

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Angie L Bookout, Bryn M Owen, Heather L Lawrence, Xunshan Ding, David J Mangelsdorf & Steven A Kliewer

  2. Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Angie L Bookout, Syann Lee, Laurent Gautron & Joel K Elmquist

  3. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Marleen H M de Groot & Joseph S Takahashi

  4. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Marleen H M de Groot, Joseph S Takahashi & David J Mangelsdorf

  5. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Xunshan Ding & Steven A Kliewer

Authors
  1. Angie L Bookout
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marleen H M de Groot
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bryn M Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Syann Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laurent Gautron
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Heather L Lawrence
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xunshan Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Joel K Elmquist
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joseph S Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David J Mangelsdorf
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Steven A Kliewer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/nm.3249

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3249

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research