Skip to main content

Thank you for visiting 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:

A PPARγ–FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis


Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood1,2. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs3,4,5. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes6. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions7,8,9. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.

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

Access options

Buy this article

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

Figure 1: FGF1A is induced in adipose tissue by an HFD.
Figure 2: Loss of FGF1 results in diet-induced insulin resistance.
Figure 3: Loss of FGF1 results in defects in adipose remodelling during HFD.
Figure 4: FGF1 is a direct transcriptional target of PPARγ.

Similar content being viewed by others

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data sets have been deposited in the NCBI Gene Expression Omnibus, accession number GSE31692.


  1. Lee, M. J., Wu, Y. & Fried, S. K. Adipose tissue remodeling in pathophysiology of obesity. Curr. Opin. Clin. Nutr. Metab. Care 13, 371–376 (2010)

    Article  Google Scholar 

  2. Sun, K., Kusminski, C. M. & Scherer, P. E. Adipose tissue remodeling and obesity. J. Clin. Invest. 121, 2094–2101 (2011)

    Article  CAS  Google Scholar 

  3. Forman, B. M. et al. 15-Deoxy-Δ12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ. Cell 83, 803–812 (1995)

    Article  CAS  Google Scholar 

  4. Barak, Y. et al. PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999)

    Article  CAS  Google Scholar 

  5. Tontonoz, P. & Spiegelman, B. M. Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77, 289–312 (2008)

    Article  CAS  Google Scholar 

  6. Itoh, N. & Ornitz, D. M. Functional evolutionary history of the mouse Fgf gene family. Dev. Dyn. 237, 18–27 (2008)

    Article  CAS  Google Scholar 

  7. Miller, D. L., Ortega, S., Bashayan, O., Basch, R. & Basilico, C. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol. Cell. Biol. 20, 2260–2268 (2000)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Myers, R. L., Payson, R. A., Chotani, M. A., Deaven, L. L. & Chiu, I. M. Gene structure and differential expression of acidic fibroblast growth factor mRNA: identification and distribution of four different transcripts. Oncogene 8, 341–349 (1993)

    CAS  PubMed  Google Scholar 

  11. Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006)

    Article  CAS  Google Scholar 

  12. Kamei, N. et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J. Biol. Chem. 281, 26602–26614 (2006)

    Article  CAS  Google Scholar 

  13. Gesta, S., Tseng, Y. H. & Kahn, C. R. Developmental origin of fat: tracking obesity to its source. Cell 131, 242–256 (2007)

    Article  CAS  Google Scholar 

  14. Schmitz-Moormann, P., von Wedel, R., Agricola, B. & Himmelmann, G. W. Studies of lipase-induced fat necrosis in rats. Pathol. Res. Pract. 163, 93–108 (1978)

    Article  CAS  Google Scholar 

  15. Lee, P. C., Nakashima, Y., Appert, H. E. & Howard, J. M. Lipase and colipase in canine pancreatic juice as etiologic factors in fat necrosis. Surg. Gynecol. Obstet. 148, 39–44 (1979)

    CAS  PubMed  Google Scholar 

  16. Chua, F. & Laurent, G. J. Neutrophil elastase: mediator of extracellular matrix destruction and accumulation. Proc. Am. Thorac. Soc. 3, 424–427 (2006)

    Article  CAS  Google Scholar 

  17. Barish, G. D., Narkar, V. A. & Evans, R. M. PPARδ: a dagger in the heart of the metabolic syndrome. J. Clin. Invest. 116, 590–597 (2006)

    Article  CAS  Google Scholar 

  18. Sugii, S. et al. PPARγ activation in adipocytes is sufficient for systemic insulin sensitization. Proc. Natl Acad. Sci. USA 106, 22504–22509 (2009)

    Article  ADS  CAS  Google Scholar 

  19. Lefterova, M. I. et al. Cell-specific determinants of peroxisome proliferator-activated receptor γ function in adipocytes and macrophages. Mol. Cell. Biol. 30, 2078–2089 (2010)

    Article  CAS  Google Scholar 

  20. He, W. et al. Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl Acad. Sci. USA 100, 15712–15717 (2003)

    Article  ADS  CAS  Google Scholar 

  21. Hutley, L. et al. Fibroblast growth factor 1: a key regulator of human adipogenesis. Diabetes 53, 3097–3106 (2004)

    Article  CAS  Google Scholar 

  22. Hutley, L. J. et al. A putative role for endogenous FGF-2 in FGF-1 mediated differentiation of human preadipocytes. Mol. Cell. Endocrinol. 339, 165–171 (2011)

    Article  CAS  Google Scholar 

  23. 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 

  24. Moore, D. D. Physiology. Sister act. Science 316, 1436–1438 (2007)

    Article  CAS  Google Scholar 

  25. Kliewer, S. A. & Mangelsdorf, D. J. Fibroblast growth factor 21: from pharmacology to physiology. Am. J. Clin. Nutr. 91, 254S–257S (2010)

    Article  CAS  Google Scholar 

  26. Kharitonenkov, A. FGFs and metabolism. Curr. Opin. Pharmacol. 9, 805–810 (2009)

    Article  CAS  Google Scholar 

  27. Fang, S. et al. Corepressor SMRT promotes oxidative phosphorylation in adipose tissue and protects against diet-induced obesity and insulin resistance. Proc. Natl Acad. Sci. USA 108, 3412–3417 (2011)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  29. Nofsinger, R. R. et al. SMRT repression of nuclear receptors controls the adipogenic set point and metabolic homeostasis. Proc. Natl Acad. Sci. USA 105, 20021–20026 (2008)

    Article  ADS  Google Scholar 

  30. Barish, G. D. et al. Bcl-6 and NF-κB cistromes mediate opposing regulation of the innate immune response. Genes Dev. 24, 2760–2765 (2010)

    Article  CAS  Google Scholar 

  31. Springer, M. L., Ip, T. K. & Blau, H. M. Angiogenesis monitored by perfusion with a space-filling microbead suspension. Mol. Ther. 1, 82–87 (2000)

    Article  CAS  Google Scholar 

Download references


We thank J. Alvarez, S. Kaufman, N. H. Uhlenhaut, M. Hassan and E. Williams for technical assistance, and L. Ong and S. Ganley for administrative assistance. R.M.E. is an Investigator of the Howard Hughes Medical Institute at the Salk Institute and March of Dimes Chair in Molecular and Developmental Biology. This work was supported by National Institutes of Health grants (DK062434, DK057978, DK090962, DK063491 and HL105278), the Helmsley Charitable Trust, and the Howard Hughes Medical Institute. J.W.J. is supported by the Human Frontier Science Program (HFSP), the Netherlands Organization for Scientific Research (NWO) and an EU Marie Curie Reintegration grant (IRG-277169). M.A. is supported by an F32 Ruth L. Kirschstein National Research Service Award (NIDDK).

Author information

Authors and Affiliations



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

Corresponding authors

Correspondence to Michael Downes or Ronald M. Evans.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-8 and Supplementary Tables 1-3. (PDF 14267 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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.


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