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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.

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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.

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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.).

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Correspondence to Allan Z Zhao.

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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)

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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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