Subjects

  • A Corrigendum to this article was published on 04 March 2015

Abstract

Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation1,2. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis3,4. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & The FGF family: biology, pathophysiology and therapy. Nature Rev. Drug Discov. 8, 235–253 (2009)

  2. 2.

    & Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease. J. Biochem. 149, 121–130 (2011)

  3. 3.

    et al. A PPARγ–FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis. Nature 485, 391–394 (2012)

  4. 4.

    & The PPARγ–FGF1 axis: an unexpected mediator of adipose tissue homeostasis. Cell Res. 22, 1416–1418 (2012)

  5. 5.

    & The many faces of PPARγ. Cell 123, 993–999 (2005)

  6. 6.

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

  7. 7.

    et al. Fibroblast growth factor-21 regulates PPARγ activity and the antidiabetic actions of thiazolidinediones. Cell 148, 556–567 (2012)

  8. 8.

    et al. Imaging Tc-99m-labeled FGF-1 targeting in rats. Nucl. Med. Biol. 27, 407–414 (2000)

  9. 9.

    & The interaction between thermodynamic stability and buried free cysteines in regulating the functional half-life of fibroblast growth factor-1. J. Mol. Biol. 393, 113–127 (2009)

  10. 10.

    et al. Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1. Sci. Transl. Med. 3, 113ra126 (2011)

  11. 11.

    , , , & Strong suppression of feeding by a peptide containing both the nuclear localization sequence of fibroblast growth factor-1 and a cell membrane-permeable sequence. Neurosci. Lett. 255, 41–44 (1998)

  12. 12.

    et al. Feeding suppression by fibroblast growth factor-1 is accompanied by selective induction of heat shock protein 27 in hypothalamic astrocytes. Eur. J. Neurosci. 13, 2299–2308 (2001)

  13. 13.

    et al. Effects of fibroblast growth factors and related peptides on food intake by rats. Physiol. Behav. 56, 211–218 (1994)

  14. 14.

    et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc. Natl Acad. Sci. USA 109, 3143–3148 (2012)

  15. 15.

    et al. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab. 17, 790–797 (2013)

  16. 16.

    et al. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab. 17, 779–789 (2013)

  17. 17.

    et al. Muscle-specific Pparg deletion causes insulin resistance. Nature Med. 9, 1491–1497 (2003)

  18. 18.

    et al. Quantification of hepatic carbohydrate metabolism in conscious mice using serial blood and urine spots. Anal. Biochem. 322, 1–13 (2003)

Download references

Acknowledgements

We thank L. Chong, J. Alvarez, S. Kaufman, B. Collins, X. Zhao, S. Liu, A. Jurdzinski, A. Bleeker, K. Bijsterveld, D. Oh and G. Bandyopadhyay for technical assistance, and L. Ong and C. Brondos for administrative assistance. Computed tomography was performed at the Veterans Medical Research Foundation. R.M.E. is a Howard Hughes Medical Institute Investigator at the Salk Institute and March of Dimes Chair, and is supported by National Institutes of Health (NIH) grants (DK057978, DK090962, HL088093, HL105278 and ES010337), the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, the California Institute for Regenerative Medicine and The Ellison Medical Foundation. C.L. and M.D. are funded by the National Health and Medical Research Council (grants 512354, 632886 and 1043199); J.W.J. by the European Research Council (grant IRG-277169), the Human Frontier Science Program (CDA00013/2011-C), the Netherlands Organisation for Scientific Research (VIDI grant 016.126.338), the Dutch Digestive Foundation (grant WO 11-67) and the Dutch Diabetes Foundation (grant 2012.00.1537); J.M.O. by NIH grants (DK-033651, DK-074868, T32-DK-007494, DK-063491 and P01-DK054441-14A1) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH through cooperative agreement of U54-HD-012303-25 as part of the specialized Cooperative Centers Program in Reproduction and Infertility Research; M.M. by the National Institute of Dental and Craniofacial Research grant (DE13686); and M.A. by an F32 Ruth L. Kirschstein National Research Service Award (National Institute of Diabetes and Digestive and Kidney Diseases).

Author information

Author notes

    • Jae Myoung Suh
    •  & Johan W. Jonker

    These authors contributed equally to this work.

    • Zhifeng Huang

    Present address: School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

Affiliations

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Jae Myoung Suh
    • , Maryam Ahmadian
    • , Eiji Yoshihara
    • , Weiwei Fan
    • , Yun-Qiang Yin
    • , Ruth T. Yu
    • , Annette R. Atkins
    • , Michael Downes
    •  & Ronald M. Evans
  2. Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

    • Johan W. Jonker
    • , Weilin Liu
    • , Theo H. van Dijk
    •  & Rick Havinga
  3. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA

    • Regina Goetz
    • , Zhifeng Huang
    •  & Moosa Mohammadi
  4. Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA

    • Denise Lackey
    • , Olivia Osborn
    •  & Jerrold M. Olefsky
  5. The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia

    • Christopher Liddle
  6. Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037, USA

    • Ronald M. Evans

Authors

  1. Search for Jae Myoung Suh in:

  2. Search for Johan W. Jonker in:

  3. Search for Maryam Ahmadian in:

  4. Search for Regina Goetz in:

  5. Search for Denise Lackey in:

  6. Search for Olivia Osborn in:

  7. Search for Zhifeng Huang in:

  8. Search for Weilin Liu in:

  9. Search for Eiji Yoshihara in:

  10. Search for Theo H. van Dijk in:

  11. Search for Rick Havinga in:

  12. Search for Weiwei Fan in:

  13. Search for Yun-Qiang Yin in:

  14. Search for Ruth T. Yu in:

  15. Search for Christopher Liddle in:

  16. Search for Annette R. Atkins in:

  17. Search for Jerrold M. Olefsky in:

  18. Search for Moosa Mohammadi in:

  19. Search for Michael Downes in:

  20. Search for Ronald M. Evans in:

Contributions

J.M.S., J.W.J. M.D. and R.M.E. designed and supervised the research. J.M.S., J.W.J., M.A., R.G., D.L., O.O., Z.H., W.L., E.Y., T.H.D., R.H., W.F., Y.-Q.Y. and A.R.A. performed research. J.M.S., J.W.J., M.A., R.T.Y., C.L., A.R.A., J.M.O., M.M., M.D. and R.M.E. analysed data. J.M.S., J.W.J., M.A., R.G., A.R.A., M.D. and R.M.E. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michael Downes or Ronald M. Evans.

Extended data

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature13540

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.