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FGF21 contributes to neuroendocrine control of female reproduction


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.

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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.


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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




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.

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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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Owen, B., Bookout, A., Ding, X. et al. FGF21 contributes to neuroendocrine control of female reproduction. Nat Med 19, 1153–1156 (2013).

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