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.

FGF21 contributes to neuroendocrine control of female reproduction

Abstract

Preventing reproduction during nutritional deprivation is an adaptive process that is conserved and essential for the survival of species. In mammals, the mechanisms that inhibit fertility during starvation are complex and incompletely understood1,2,3,4,5,6,7. Here we show that exposure of female mice to fibroblast growth factor 21 (FGF21), a fasting-induced hepatokine, mimics infertility secondary to starvation. Mechanistically, FGF21 acts on the suprachiasmatic nucleus (SCN) in the hypothalamus to suppress the vasopressin-kisspeptin signaling cascade, thereby inhibiting the proestrus surge in luteinizing hormone. Mice lacking the FGF21 co-receptor, β-Klotho, in the SCN are refractory to the inhibitory effect of FGF21 on female fertility. Thus, FGF21 defines an important liver-neuroendocrine axis that modulates female reproduction in response to nutritional challenge.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Female Tg(Fgf21) mice are infertile.
Figure 2: Female Tg(Fgf21) mice display hypothalamic hypogonadism.
Figure 3: Klb expression in the hypothalamus is essential for FGF21-mediated effects on ovulation.
Figure 4: Evidence that FGF21 modulates female reproduction as part of the adaptive starvation response.

References

  1. 1

    Burks, D.J. et al. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 407, 377–382 (2000).

    CAS  Article  Google Scholar 

  2. 2

    Chehab, F.F., Lim, M.E. & Lu, R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin. Nat. Genet. 12, 318–320 (1996).

    CAS  Article  Google Scholar 

  3. 3

    Della Torre, S. et al. Amino acid–dependent activation of liver estrogen receptor α integrates metabolic and reproductive functions via IGF-1. Cell Metab. 13, 205–214 (2011).

    CAS  Article  Google Scholar 

  4. 4

    Altarejos, J.Y. et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nat. Med. 14, 1112–1117 (2008).

    CAS  Article  Google Scholar 

  5. 5

    Kalamatianos, T., Grimshaw, S.E., Poorun, R., Hahn, J.D. & Coen, C.W. Fasting reduces KiSS-1 expression in the anteroventral periventricular nucleus (AVPV): effects of fasting on the expression of KiSS-1 and neuropeptide Y in the AVPV or arcuate nucleus of female rats. J. Neuroendocrinol. 20, 1089–1097 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Roa, J. et al. The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 150, 5016–5026 (2009).

    CAS  Article  Google Scholar 

  7. 7

    Brüning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    Article  Google Scholar 

  8. 8

    Goetz, R. et al. Molecular insights into the Klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell Biol. 27, 3417–3428 (2007).

    CAS  Article  Google Scholar 

  9. 9

    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).

    CAS  Article  Google Scholar 

  10. 10

    Gälman, C. et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARα activation in man. Cell Metab. 8, 169–174 (2008).

    Article  Google Scholar 

  11. 11

    Hondares, E. et al. Hepatic FGF21 expression is induced at birth via PPARα in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab. 11, 206–212 (2010).

    CAS  Article  Google Scholar 

  12. 12

    Kharitonenkov, A. et al. FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115, 1627–1635 (2005).

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  Article  Google Scholar 

  14. 14

    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).

    CAS  Article  Google Scholar 

  15. 15

    Zhang, Y. et al. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife 1, e00065.

  16. 16

    Roa, J., Navarro, V.M. & Tena-Sempere, M. Kisspeptins in reproductive biology: consensus knowledge and recent developments. Biol. Reprod. 85, 650–660 (2011).

    CAS  Article  Google Scholar 

  17. 17

    Mayer, C. et al. Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons. Proc. Natl. Acad. Sci. USA 107, 22693–22698 (2010).

    CAS  Article  Google Scholar 

  18. 18

    Miller, B.H. et al. Vasopressin regulation of the proestrous luteinizing hormone surge in wild-type and Clock mutant mice. Biol. Reprod. 75, 778–784 (2006).

    CAS  Article  Google Scholar 

  19. 19

    Vida, B. et al. Evidence for suprachiasmatic vasopressin neurones innervating kisspeptin neurones in the rostral periventricular area of the mouse brain: regulation by oestrogen. J. Neuroendocrinol. 22, 1032–1039 (2010).

    CAS  Article  Google Scholar 

  20. 20

    Roa, J. et al. Kisspeptins and the control of gonadotropin secretion in male and female rodents. Peptides 30, 57–66 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Clarkson, J. & Herbison, A.E. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147, 5817–5825 (2006).

    CAS  Article  Google Scholar 

  22. 22

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

    CAS  Article  Google Scholar 

  23. 23

    Bookout, A.L. et al. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat. Med. advance online publication, 10.1038/nm.3249 (11 August 2013).

  24. 24

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

    CAS  Article  Google Scholar 

  25. 25

    Kalsbeek, A., Buijs, R.M., van Heerikhuize, J.J., Arts, M. & van der Woude, T.P. Vasopressin-containing neurons of the suprachiasmatic nuclei inhibit corticosterone release. Brain Res. 580, 62–67 (1992).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

    Cardozo, E., Pavone, M.E. & Hirshfeld-Cytron, J.E. Metabolic syndrome and oocyte quality. Trends Endocrinol. Metab. 22, 103–109 (2011).

    CAS  Article  Google Scholar 

  28. 28

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

    CAS  Article  Google Scholar 

  29. 29

    Caligioni, C.S. Assessing reproductive status/stages in mice. Curr. Protoc. Neurosci. Appendix 4I (2009).

  30. 30

    Quennell, J.H. et al. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology 152, 1541–1550 (2011).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank our colleagues at the University of Texas Southwestern Medical Center, R. Hammer and members of the Mangelsdorf/Kliewer laboratory for discussion, Y. Zhang, H. Lawrence and L. Harris for technical assistance, J. Shelton for imaging; and R. Goetz and M. Mohammadi (New York University) for FGF21 protein. This research was supported by the Howard Hughes Medical Institute (D.J.M.), US National Institutes of Health grants RL1GM084436, R01DK067158, and R56DK089600 (to D.J.M. and S.A.K.), U19DK62434 (to D.J.M.) and GM007062 (to A.L.B.) and the Robert A. Welch Foundation (I-1275 to D.J.M. and I-1558 to S.A.K.). The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Institutes of Health (Specialized Cooperative Centers Program in Reproduction and Infertility Research (SCCPIR)) grant U54-HD28934.

Author information

Affiliations

Authors

Contributions

B.M.O. designed and performed all experiments, analyzed data and wrote the paper. A.L.B. generated Klbtm1(Camk2a); Tg(Fgf21) and Klbtm1(Phox2b); Tg(Fgf21) mice and designed and performed experiments. X.D. generated Klbtm1 mice. V.Y.L., S.D.A. and L.G. performed experiments and analyzed data. D.J.M. and S.A.K. supervised the project and wrote the paper.

Corresponding authors

Correspondence to Steven A Kliewer or David J Mangelsdorf.

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 1–3 (PDF 3211 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Owen, B., Bookout, A., Ding, X. et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 19, 1153–1156 (2013). https://doi.org/10.1038/nm.3250

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing