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Nature Medicine 12, 425 - 432 (2006)
Published online: 2 April 2006 | doi:10.1038/nm1372

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

Ke Chen1,6, Fanghong Li1,6, Ji Li1, Hongbo Cai2, Steven Strom2, Alessandro Bisello3, David E Kelley3, Miriam Friedman-Einat4, Gregory A Skibinski5, Mark A McCrory5, Alexander J Szalai5 & Allan Z Zhao1


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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