Skip to main content

Thank you for visiting nature.com. 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.

  • Article
  • Published:

Tissue factor–protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation

Nature Medicine volume 17, pages 1490–1497 (2011)Cite this article

Subjects

Abstract

Tissue factor, the initiator of the coagulation cascade, mediates coagulation factor VIIa–dependent activation of protease-activated receptor 2 (PAR2). Here we delineate a role for this signaling pathway in obesity and its complications. Mice lacking PAR2 (F2rl1) or the cytoplasmic domain of tissue factor were protected from weight gain and insulin resistance induced by a high-fat diet. In hematopoietic cells, genetic ablation of tissue factor–PAR2 signaling reduced adipose tissue macrophage inflammation, and specific pharmacological inhibition of macrophage tissue factor signaling rapidly ameliorated insulin resistance. In contrast, nonhematopoietic cell tissue factor–VIIa-PAR2 signaling specifically promoted obesity. Mechanistically, adipocyte tissue factor cytoplasmic domain–dependent VIIa signaling suppressed Akt phosphorylation with concordant adverse transcriptional changes of key regulators of obesity and metabolism. Pharmacological blockade of adipocyte tissue factor in vivo reversed these effects of tissue factor–VIIa signaling and rapidly increased energy expenditure. Thus, inhibition of tissue factor signaling is a potential therapeutic avenue for improving impaired metabolism and insulin resistance in obesity.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Tissue factor–PAR2 signaling promotes diet-induced obesity and insulin resistance.
Figure 2: Tissue factor–PAR2 signaling in hematopoietic cells contributes to insulin resistance and adipose tissue macrophage inflammation.
Figure 3: Pharmacological inhibition of hematopoietic tissue factor–PAR2 signaling ameliorates insulin resistance and adipose tissue macrophage inflammation.
Figure 4: Tissue factor–PAR2 signaling in nonhematopoietic cells contributes to DIO.
Figure 5: Contributions of adipocyte tissue factor–PAR2 signaling to regulation of glucose and lipid metabolism in obesity.
Figure 6: Schematic overview of the contributions of macrophage and adipocyte tissue factor–PAR2 signaling to insulin resistance and obesity.

Similar content being viewed by others

References

  1. Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Oh, D.Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Ouchi, N. et al. Sfrp5 is an anti-inflammatory adipokine that modulates metabolic dysfunction in obesity. Science 329, 454–457 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Odegaard, J.I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Rajagopal, S., Rajagopal, K. & Lefkowitz, R.J. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat. Rev. Drug Discov. 9, 373–386 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. Wang, P. & DeFea, K.A. Protease-activated receptor-2 simultaneously directs β-arrestin-1–dependent inhibition and Gαq-dependent activation of phosphatidylinositol 3-kinase. Biochemistry 45, 9374–9385 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Luan, B. et al. Deficiency of a β-arrestin-2 signal complex contributes to insulin resistance. Nature 457, 1146–1149 (2009).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, P., Kumar, P., Wang, C. & DeFea, K.A. Differential regulation of class IA phosphoinositide 3-kinase catalytic subunits p110 α and β by protease-activated receptor 2 and β-arrestins. Biochem. J. 408, 221–230 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Zoudilova, M. et al. β-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2. J. Biol. Chem. 282, 20634–20646 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Wang, P., Jiang, Y., Wang, Y., Shyy, J.Y. & DeFea, K.A. β-arrestin inhibits CAMKKβ-dependent AMPK activation downstream of protease-activated-receptor-2. BMC Biochem. 11, 36 (2010).

    Article  PubMed  Google Scholar 

  13. Hotamisligil, G.S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  Google Scholar 

  14. De Taeye, B., Smith, L.H. & Vaughan, D.E. Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease. Curr. Opin. Pharmacol. 5, 149–154 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Gerrits, A.J., Koekman, C.A., Haeften, V.A.N.T.W. & Akkerman, J.W. Increased tissue factor expression in diabetes mellitus type 2 monocytes caused by insulin resistance. J. Thromb. Haemost. 9, 873–875 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Diamant, M. et al. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation 106, 2442–2447 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Kopp, C.W. et al. Weight loss reduces tissue factor in morbidly obese patients. Obes. Res. 11, 950–956 (2003).

    Article  PubMed  Google Scholar 

  18. Samad, F., Pandey, M. & Loskutoff, D.J. Tissue factor gene expression in the adipose tissues of obese mice. Proc. Natl. Acad. Sci. USA 95, 7591–7596 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Dorfleutner, A., Hintermann, E., Tarui, T., Takada, Y. & Ruf, W. Cross-talk of integrin α3β1 and tissue factor in cell migration. Mol. Biol. Cell 15, 4416–4425 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Schaffner, F. et al. Cooperation of tissue factor cytoplasmic domain and PAR2 signaling in breast cancer development. Blood 116, 6106–6113 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Redecha, P., Franzke, C.W., Ruf, W., Mackman, N. & Girardi, G. Neutrophil activation by the tissue factor/factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome. J. Clin. Invest. 118, 3453–3461 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Ahamed, J. et al. Disulfide isomerization switches tissue factor from coagulation to cell signaling. Proc. Natl. Acad. Sci. USA 103, 13932–13937 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Versteeg, H.H. et al. Inhibition of tissue factor signaling suppresses tumor growth. Blood 111, 190–199 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Olefsky, J.M. & Glass, C.K. Macrophages, inflammation and insulin resistance. Annu. Rev. Physiol. 72, 219–246 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Patsouris, D. et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8, 301–309 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Cinti, S. et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J. Lipid Res. 46, 2347–2355 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Guha, M. & Mackman, N. LPS induction of gene expression in human monocytes. Cell Signal. 13, 85–94 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Randolph, G.J., Luther, T., Albrecht, S., Magdolen, V. & Muller, W.A. Role of tissue factor in adhesion of mononuclear phagocytes to and trafficking through endothelium in vitro. Blood 92, 4167–4177 (1998).

    CAS  PubMed  Google Scholar 

  29. Ahamed, J. et al. Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia. Blood 109, 5251–5259 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Noorbakhsh, F. et al. Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis. J. Exp. Med. 203, 425–435 (2006).

    Article  PubMed  Google Scholar 

  31. Odegaard, J.I. et al. Alternative M2 activation of Kupffer cells by PPARδ ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Saberi, M. et al. Hematopoietic cell-specific deletion of Toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 10, 419–429 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Liu, L. et al. Upregulation of myocellular DGAT1 augments triglyceride synthesis in skeletal muscle and protects against fat-induced insulin resistance. J. Clin. Invest. 117, 1679–1689 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Pickersgill, L., Litherland, G.J., Greenberg, A.S., Walker, M. & Yeaman, S.J. Key role for ceramides in mediating insulin resistance in human muscle cells. J. Biol. Chem. 282, 12583–12589 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Snyder, L.A. et al. Expression of human tissue factor under the control of the mouse tissue factor promoter mediates normal hemostasis in knock-in mice. J. Thromb. Haemost. 6, 306–314 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Bradshaw, G. et al. Facilitated replacement of Kupffer cells expressing a paraoxonase-1 transgene is essential for ameliorating atherosclerosis in mice. Proc. Natl. Acad. Sci. USA 102, 11029–11034 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Mackman, N., Sawdey, M.S., Keeton, M.R. & Loskutoff, D.J. Murine tissue factor gene expression in vivo: tissue and cell specificity and regulation by lipopolysaccharide. Am. J. Pathol. 143, 76–84 (1993).

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Samad, F., Pandey, M. & Loskutoff, D.J. Regulation of tissue factor gene expression in obesity. Blood 98, 3353–3358 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Venugopal, J., Hanashiro, K., Yang, Z.Z. & Nagamine, Y. Identification and modulation of a caveolae-dependent signal pathway that regulates plasminogen activator inhibitor-1 in insulin-resistant adipocytes. Proc. Natl. Acad. Sci. USA 101, 17120–17125 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Kidani, T. et al. Bisphenol A downregulates Akt signaling and inhibits adiponectin production and secretion in 3T3–L1 adipocytes. J. Atheroscler. Thromb. 17, 834–843 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Matsuzawa, Y. Adiponectin: a key player in obesity related disorders. Curr. Pharm. Des. 16, 1896–1901 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Qi, Y. et al. Adiponectin acts in the brain to decrease body weight. Nat. Med. 10, 524–529 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Jäger, S., Handschin, C., St-Pierre, J. & Spiegelman, B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl. Acad. Sci. USA 104, 12017–12022 (2007).

    Article  PubMed  Google Scholar 

  45. Lee, Y. et al. PPAR α is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue. Proc. Natl. Acad. Sci. USA 99, 11848–11853 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Uysal, K.T., Wiesbrock, S.M., Marino, M.W. & Hotamisligil, G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Guerre-Millo, M. et al. Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity. J. Biol. Chem. 275, 16638–16642 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Surwit, R.S. et al. Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. Proc. Natl. Acad. Sci. USA 95, 4061–4065 (1998).

    Article  CAS  PubMed  Google Scholar 

  49. Fleury, C. et al. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat. Genet. 15, 269–272 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-α: Direct role in obesity-linked insulin resistance. Science 259, 87–91 (1993).

    Article  CAS  PubMed  Google Scholar 

  51. Hotamisligil, G.S., Budavari, A., Murray, D. & Spiegelman, B.M. Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-α. J. Clin. Invest. 94, 1543–1549 (1994).

    Article  CAS  PubMed  Google Scholar 

  52. Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Lumeng, C.N., Bodzin, J.L. & Saltiel, A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117, 175–184 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Steinbrecher, K.A. et al. Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin αMβ2 engagement of fibrinogen. Cancer Res. 70, 2634–2643 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Smiley, S.T., King, J.A. & Hancock, W.W. Fibrinogen stimulates macrophage chemokine secretion through Toll-like receptor 4. J. Immunol. 167, 2887–2894 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Flick, M.J. et al. Leukocyte engagement of fibrin(ogen) via the integrin receptor αMβ2/Mac-1 is critical for host inflammatory response in vivo. J. Clin. Invest. 113, 1596–1606 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Melis, E. et al. Targeted deletion of the cytosolic domain of tissue factor in mice does not affect development. Biochem. Biophys. Res. Commun. 286, 580–586 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Damiano, B.P. et al. Cardiovascular responses mediated by protease-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1. J. Pharmacol. Exp. Ther. 288, 671–678 (1999).

    CAS  PubMed  Google Scholar 

  59. Yang, G. et al. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab. 297, E211–E224 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Samad, F., Yamamoto, K. & Loskutoff, D.J. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-α and lipopolysaccharide. J. Clin. Invest. 97, 37–46 (1996).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by US National Institutes of Health grants HL71146, HL104232 (F.S.) and HL77753 (W.R.), a grant from the Diabetes National Research Group (F.S.) and a postdoctoral fellowship from the American Heart Association (C.F.-F.). We thank M. Anderson (Johnson & Johnson Pharmaceutical Research and Development, Radnor, Pennsylvania, USA) for TFKI mice, C. Biazak, J. Royce, N. Vu and R. Zubairi for technical assistance, A.J. Roberts for assistance with metabolic studies and C. Johnson for preparation of figures.

Author information

Author notes

  1. Leylla Badeanlou and Christian Furlan-Freguia: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Biology, Torrey Pines Institute for Molecular Studies, San Diego, California, USA

    Leylla Badeanlou, Guang Yang & Fahumiya Samad

  2. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA

    Christian Furlan-Freguia & Wolfram Ruf

Authors
  1. Leylla Badeanlou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christian Furlan-Freguia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wolfram Ruf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fahumiya Samad
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.B. carried out metabolic, gene expression and in vitro experiments and analyzed data. C.F.-F. generated bone marrow chimeras, carried out FACS analysis and analyzed data. G.Y. carried out in vivo and in vitro Akt activation assays. W.R. and F.S. designed experiments, analyzed data, wrote the manuscript and share the last authorship.

Corresponding authors

Correspondence to Wolfram Ruf or Fahumiya Samad.

Ethics declarations

Competing interests

W.R. and F.S. have a US patent application on the use of tissue factor–specific antibodies to ameliorate insulin resistance and obesity.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 616 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Badeanlou, L., Furlan-Freguia, C., Yang, G. et al. Tissue factor–protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med 17, 1490–1497 (2011). https://doi.org/10.1038/nm.2461

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2461

This article is cited by

Search

Advanced search

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