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 through your institution Buy or

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INTRA-PITUITARY FOLLICLE-STIMULATING HORMONE SIGNALING REGULATES HEPATIC LIPID METABOLISM IN MICE Article Open access 25 February 2023 GNRH2 MAINTAINS REPRODUCTION IN FASTING ZEBRAFISH

THROUGH DYNAMIC NEURONAL PROJECTION CHANGES AND REGULATION OF GONADOTROPIN SYNTHESIS, OOGENESIS, AND REPRODUCTIVE BEHAVIORS Article Open access 23 March 2021 SELECTIVE EFFECTS OF PROTEIN

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expression in mice. _Endocrinology_ 152, 1541–1550 (2011). Article  CAS  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 Author notes *

[email protected] AUTHORS AND AFFILIATIONS * Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Bryn M Owen, Angie L Bookout, Xunshan

Ding, Vicky Y Lin, Stan D Atkin, Steven A Kliewer & David J Mangelsdorf * Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical

Center, Dallas, Texas, USA Angie L Bookout & Laurent Gautron * Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Xunshan Ding & 

Steven A Kliewer * Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA David J Mangelsdorf Authors * Bryn M Owen View author publications You

can also search for this author inPubMed Google Scholar * Angie L Bookout View author publications You can also search for this author inPubMed Google Scholar * Xunshan Ding View author

publications You can also search for this author inPubMed Google Scholar * Vicky Y Lin View author publications You can also search for this author inPubMed Google Scholar * Stan D Atkin

View author publications You can also search for this author inPubMed Google Scholar * Laurent Gautron View author publications You can also search for this author inPubMed Google Scholar *

Steven A Kliewer View author publications You can also search for this author inPubMed Google Scholar * David J Mangelsdorf View author publications You can also search for this author

inPubMed Google Scholar CONTRIBUTIONS B.M.O. designed and performed all experiments, analyzed data and wrote the paper. A.L.B. generated _Klb__tm1(Camk2a)_; Tg(Fgf21) and _Klb__tm1(Phox2b)_;

Tg(Fgf21) mice and designed and performed experiments. X.D. generated _Klb__tm1_ 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 * Received: 29 March 2013 * Accepted: 29 May 2013 * Published: 11 August 2013 * Issue Date: September 2013 * DOI:

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