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

Nature volume 485, pages 391–394 (2012)Cite this article

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Abstract

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.

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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.

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Gene Expression Omnibus

Data deposits

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

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Acknowledgements

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).

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Author notes

  1. Johan W. Jonker

    Present address: Present address: Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.,

  2. Johan W. Jonker and Jae Myoung Suh: These authors contributed equally to this work.

Authors and Affiliations

  1. Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,

    Johan W. Jonker, Jae Myoung Suh, Annette R. Atkins, Maryam Ahmadian, Jamie Whyte, Mingxiao He, Henry Juguilon, Yun-Qiang Yin, Colin T. Phillips, Ruth T. Yu, Michael Downes & Ronald M. Evans

  2. Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, 92093, California, USA

    Pingping Li, Jerrold M. Olefsky & Robert R. Henry

  3. Section of Diabetes/Metabolism, Veterans Affairs San Diego Healthcare System, San Diego, 92161, California, USA

    Robert R. Henry

  4. Howard Hughes Medical Institute, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA ,

    Ronald M. Evans

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Contributions

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.

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The authors declare no competing financial interests.

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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). https://doi.org/10.1038/nature10998

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