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.

Induction of leptin resistance through direct interaction of C-reactive protein with leptin

Abstract

The mechanisms underlying leptin resistance are still being defined. We report here the presence in human blood of several serum leptin-interacting proteins (SLIPs), isolated by leptin-affinity chromatography and identified by mass spectrometry and immunochemical analysis. We confirmed that one of the major SLIPs is C-reactive protein (CRP). In vitro, human CRP directly inhibits the binding of leptin to its receptors and blocks its ability to signal in cultured cells. In vivo, infusion of human CRP into ob/ob mice blocked the effects of leptin upon satiety and weight reduction. In mice that express a transgene encoding human CRP, the actions of human leptin were completely blunted. We also found that physiological concentrations of leptin can stimulate expression of CRP in human primary hepatocytes. Recently, human CRP has been correlated with increased adiposity and plasma leptin. Thus, our results suggest a potential mechanism contributing to leptin resistance, by which circulating CRP binds to leptin and attenuates its physiological functions.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Purification of SLIPs and identification of SLIP-1.
Figure 2: Determination of CRP and leptin interaction.
Figure 3: The effects of human or rat CRP on leptin signaling.
Figure 4: The effects of human CRP on the physiological functions of human leptin in ob/ob mice.
Figure 5: Infusion or transgenic expression of human CRP attenuates the physiological functions of human leptin.
Figure 6: The effects of human leptin and IL-6 on expression of CRP.

References

  1. Friedman, J.M. & Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).

    CAS  Article  Google Scholar 

  2. Ahima, R.S. & Flier, J.S. Leptin. Annu. Rev. Physiol. 62, 413–437 (2000).

    CAS  Article  Google Scholar 

  3. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994) [published erratum appears in Nature 374, 479 (1995)].

    CAS  Article  Google Scholar 

  4. Lee, G.H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

    CAS  Article  Google Scholar 

  5. Schwartz, M.W. et al. Evidence that plasma leptin and insulin levels are associated with body adiposity via different mechanisms. Diabetes Care 20, 1476–1481 (1997).

    CAS  Article  Google Scholar 

  6. Heymsfield, S.B. et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. J. Am. Med. Assoc. 282, 1568–1575 (1999).

    CAS  Article  Google Scholar 

  7. Gura, T. Obesity research. Leptin not impressive in clinical trial. Science 286, 881–882 (1999).

    CAS  Article  Google Scholar 

  8. Bjorbaek, C., El-Haschimi, K., Frantz, J.D. & Flier, J.S. The role of SOCS-3 in leptin signaling and leptin resistance. J. Biol. Chem. 274, 30059–30065 (1999).

    CAS  Article  Google Scholar 

  9. Tseng, J. & Mortensen, R.F. Binding of human C-reactive protein (CRP) to plasma fibronectin occurs via the phosphorylcholine-binding site. Mol. Immunol. 25, 679–686 (1988).

    CAS  Article  Google Scholar 

  10. Schulze, M.B. et al. C-reactive protein and incident cardiovascular events among men with diabetes. Diabetes Care 27, 889–894 (2004).

    CAS  Article  Google Scholar 

  11. Kazumi, T., Kawaguchi, A., Hirano, T. & Yoshino, G. C-reactive protein in young, apparently healthy men: associations with serum leptin, QTc interval, and high-density lipoprotein-cholesterol. Metabolism 52, 1113–1116 (2003).

    CAS  Article  Google Scholar 

  12. Mistrik, P., Moreau, F. & Allen, J.M. BiaCore analysis of leptin-leptin receptor interaction: evidence for 1:1 stoichiometry. Anal. Biochem. 327, 271–277 (2004).

    CAS  Article  Google Scholar 

  13. Aronson, D. et al. Obesity is the major determinant of elevated C-reactive protein in subjects with the metabolic syndrome. Int. J. Obes. Relat. Metab. Disord. 28, 674–679 (2004).

    CAS  Article  Google Scholar 

  14. de Beer, F.C. et al. Isolation and characterization of C-reactive protein and serum amyloid P component in the rat. Immunology 45, 55–70 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Vaisse, C. et al. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat. Genet. 14, 95–97 (1996).

    CAS  Article  Google Scholar 

  16. Zhao, A.Z., Huan, J.N., Gupta, S., Pal, R. & Sahu, A. A phosphatidylinositol 3-kinase phosphodiesterase 3B-cyclic AMP pathway in hypothalamic action of leptin on feeding. Nat. Neurosci. 5, 727–728 (2002).

    CAS  Article  Google Scholar 

  17. Niswender, K.D. et al. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413, 794–795 (2001).

    CAS  Article  Google Scholar 

  18. Tartaglia, L.A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).

    CAS  Article  Google Scholar 

  19. Pignatti, P. et al. High circulating levels of biologically inactive IL-6/SIL-6 receptor complexes in systemic juvenile idiopathic arthritis: evidence for serum factors interfering with the binding to gp130. Clin. Exp. Immunol. 131, 355–363 (2003).

    CAS  Article  Google Scholar 

  20. Zahedi, K. et al. Major acute-phase reactant synthesis during chronic inflammation in amyloid-susceptible and -resistant mouse strains. Inflammation 15, 1–14 (1991).

    CAS  Article  Google Scholar 

  21. Maachi, M. et al. Systemic low-grade inflammation is related to both circulating and adipose tissue TNFalpha, leptin and IL-6 levels in obese women. Int. J. Obes. Relat. Metab. Disord. 28, 993–997 (2004).

    CAS  Article  Google Scholar 

  22. Szalai, A.J. & McCrory, M.A. Varied biologic functions of C-reactive protein: lessons learned from transgenic mice. Immunol. Res. 26, 279–287 (2002).

    CAS  Article  Google Scholar 

  23. Harris, R.B. et al. A leptin dose-response study in obese (ob/ob) and lean (+/?) mice. Endocrinology 139, 8–19 (1998).

    CAS  Article  Google Scholar 

  24. Shamsuzzaman, A.S. et al. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation 109, 2181–2185 (2004).

    CAS  Article  Google Scholar 

  25. Mortensen, R.F. C-reactive protein, inflammation, and innate immunity. Immunol. Res. 24, 163–176 (2001).

    CAS  Article  Google Scholar 

  26. Yudkin, J.S., Kumari, M., Humphries, S.E. & Mohamed-Ali, V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148, 209–214 (2000).

    CAS  Article  Google Scholar 

  27. Castell, J.V. et al. Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 12, 1179–1186 (1990).

    CAS  Article  Google Scholar 

  28. Zhang, D., Sun, M., Samols, D. & Kushner, I. STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6. J. Biol. Chem. 271, 9503–9509 (1996).

    CAS  Article  Google Scholar 

  29. Ridker, P.M. High-sensitivity C-reactive protein, inflammation, and cardiovascular risk: from concept to clinical practice to clinical benefit. Am. Heart J. 148, S19–S26 (2004).

    CAS  Article  Google Scholar 

  30. Lennie, T.A., McCarthy, D.O. & Keesey, R.E. Body energy status and the metabolic response to acute inflammation. Am. J. Physiol. 269, R1024–R1031 (1995).

    CAS  PubMed  Google Scholar 

  31. McCarthy, D.O. Tumor necrosis factor alpha and interleukin-6 have differential effects on food intake and gastric emptying in fasted rats. Res. Nurs. Health 23, 222–228 (2000).

    CAS  Article  Google Scholar 

  32. Mackintosh, R.M. & Hirsch, J. The effects of leptin administration in non-obese human subjects. Obes. Res. 9, 462–469 (2001).

    CAS  Article  Google Scholar 

  33. Hukshorn, C.J. et al. Leptin and the proinflammatory state associated with human obesity. J. Clin. Endocrinol. Metab. 89, 1773–1778 (2004).

    CAS  Article  Google Scholar 

  34. Chan, J.L. et al. Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess. J. Clin. Endocrinol. Metab. 90, 1618–1624 (2005).

    CAS  Article  Google Scholar 

  35. Hukshorn, C.J. et al. The effect of pegylated recombinant human leptin (PEG-OB) on weight loss and inflammatory status in obese subjects. Int. J. Obes. Relat. Metab. Disord. 26, 504–509 (2002).

    CAS  Article  Google Scholar 

  36. Shrive, A.K. et al. Three dimensional structure of human C-reactive protein. Nat. Struct. Biol. 3, 346–354 (1996).

    CAS  Article  Google Scholar 

  37. Schwartz, M.W., Peskind, E., Raskind, M., Boyko, E.J. & Porte, D., Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat. Med. 2, 589–593 (1996).

    CAS  Article  Google Scholar 

  38. Rajs, G., Finzi-Yeheskel, Z., Rajs, A. & Mayer, M. C-reactive protein concentrations in cerebral spinal fluid in gram-positive and gram-negative bacterial meningitis. Clin. Chem. 48, 591–592 (2002).

    CAS  PubMed  Google Scholar 

  39. Sinha, M.K. et al. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting. J. Clin. Invest. 98, 1277–1282 (1996).

    CAS  Article  Google Scholar 

  40. McConway, M.G. et al. Differences in circulating concentrations of total, free and bound leptin relate to gender and body composition in adult humans. Ann. Clin. Biochem. 37, 717–723 (2000).

    CAS  Article  Google Scholar 

  41. Friedman-Einat, M. et al. Serum leptin activity in obese and lean patients. Regul. Pept. 111, 77–82 (2003).

    CAS  Article  Google Scholar 

  42. Zhao, A.Z., Zhao, H., Teague, J., Fujimoto, W. & Beavo, J.A. Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B. Proc. Natl. Acad. Sci. USA 94, 3223–3228 (1997).

    CAS  Article  Google Scholar 

  43. Huan, J.N. et al. Adipocyte-selective reduction of the leptin receptors induced by antisense RNA leads to increased adiposity, dyslipidemia, and insulin resistance. J. Biol. Chem. 278, 45638–45650 (2003).

    CAS  Article  Google Scholar 

  44. Kostrubsky, V.E. et al. The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures. Drug Metab. Dispos. 28, 1192–1197 (2000).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank A. Stewart for his critical evaluation of this manuscript. This work is supported in part by a US National Institutes of Health grant (1RO1DK064383-01) and a Career & Development award from the American Diabetes Association (to A.Z.Z.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Allan Z Zhao.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Purification scheme of SLIPs and identification of human OBR. (PDF 859 kb)

Supplementary Fig. 2

Purification of rat C-reactive protein. (PDF 1633 kb)

Supplementary Fig. 3

Quantification of leptin-induced STAT3 activation. (PDF 631 kb)

Supplementary Fig. 4

Serum concentrations of human CRP and human leptin. (PDF 804 kb)

Supplementary Fig. 5

Quantification of leptin-induced hypothalamic STAT3 activation. (PDF 563 kb)

Supplementary Table 1

Nano-LC-MS/MS in-gel protein identification of h-SLIP-1. (PDF 523 kb)

Supplementary Table 2

Identification of r-SLIP-1 with MALDI-TOF in-gel protein identification. (PDF 1374 kb)

Supplementary Note (PDF 28 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chen, K., Li, F., Li, J. et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 12, 425–432 (2006). https://doi.org/10.1038/nm1372

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1372

Further reading

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