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.
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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.).
The authors declare no competing financial interests.
Purification scheme of SLIPs and identification of human OBR. (PDF 859 kb)
Purification of rat C-reactive protein. (PDF 1633 kb)
Quantification of leptin-induced STAT3 activation. (PDF 631 kb)
Serum concentrations of human CRP and human leptin. (PDF 804 kb)
Quantification of leptin-induced hypothalamic STAT3 activation. (PDF 563 kb)
Nano-LC-MS/MS in-gel protein identification of h-SLIP-1. (PDF 523 kb)
Identification of r-SLIP-1 with MALDI-TOF in-gel protein identification. (PDF 1374 kb)
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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
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