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 via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Friedman, J.M. & Halaas, J.L. Leptin and the regulation of body weight in mammals. Nature 395, 763–770 (1998).
Ahima, R.S. & Flier, J.S. Leptin. Annu. Rev. Physiol. 62, 413–437 (2000).
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)].
Lee, G.H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).
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).
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).
Gura, T. Obesity research. Leptin not impressive in clinical trial. Science 286, 881–882 (1999).
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).
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).
Schulze, M.B. et al. C-reactive protein and incident cardiovascular events among men with diabetes. Diabetes Care 27, 889–894 (2004).
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).
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).
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).
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).
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).
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).
Niswender, K.D. et al. Intracellular signalling. Key enzyme in leptin-induced anorexia. Nature 413, 794–795 (2001).
Tartaglia, L.A. et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 83, 1263–1271 (1995).
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).
Zahedi, K. et al. Major acute-phase reactant synthesis during chronic inflammation in amyloid-susceptible and -resistant mouse strains. Inflammation 15, 1–14 (1991).
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).
Szalai, A.J. & McCrory, M.A. Varied biologic functions of C-reactive protein: lessons learned from transgenic mice. Immunol. Res. 26, 279–287 (2002).
Harris, R.B. et al. A leptin dose-response study in obese (ob/ob) and lean (+/?) mice. Endocrinology 139, 8–19 (1998).
Shamsuzzaman, A.S. et al. Independent association between plasma leptin and C-reactive protein in healthy humans. Circulation 109, 2181–2185 (2004).
Mortensen, R.F. C-reactive protein, inflammation, and innate immunity. Immunol. Res. 24, 163–176 (2001).
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).
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).
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).
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).
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).
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).
Mackintosh, R.M. & Hirsch, J. The effects of leptin administration in non-obese human subjects. Obes. Res. 9, 462–469 (2001).
Hukshorn, C.J. et al. Leptin and the proinflammatory state associated with human obesity. J. Clin. Endocrinol. Metab. 89, 1773–1778 (2004).
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).
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).
Shrive, A.K. et al. Three dimensional structure of human C-reactive protein. Nat. Struct. Biol. 3, 346–354 (1996).
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).
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).
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).
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).
Friedman-Einat, M. et al. Serum leptin activity in obese and lean patients. Regul. Pept. 111, 77–82 (2003).
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).
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).
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).
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
Corresponding author
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)
Rights 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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1372
This article is cited by
-
Effect of C-reactive protein deficiency on insulin resistance reversal in rats with polycystic ovary syndrome through augmented leptin action
Diabetology & Metabolic Syndrome (2023)
-
Associations of leptin and corticostriatal connectivity in bipolar disorder
Scientific Reports (2022)
-
Inflammation and depression in young people: a systematic review and proposed inflammatory pathways
Molecular Psychiatry (2022)
-
STAT3 phosphorylation in central leptin resistance
Nutrition & Metabolism (2021)
-
Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts
Molecular Psychiatry (2021)