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 leptinKe 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 Zhao11
Department of Cell Biology & Physiology, University of Pittsburgh, 3500 Terrace Street, BST/S-326, Pittsburgh, Pennsylvania 15261, USA. 2
Department of Pathology, University of Pittsburgh, 3500 Terrace Street, BST/S-326, Pittsburgh, Pennsylvania 15261, USA. 3
Division of Endocrinology & Bone Metabolism & Obesity and Nutrition Research Center, University of Pittsburgh, 3500 Terrace Street, BST/S-326, Pittsburgh, Pennsylvania 15261, USA. 4
Institute of Animal Science, ARO, Volcani Center, P.O. Box 6 Bet-Dagan 50-250, Israel. 5
Department of Medicine, Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, 1900 University Boulevard, THT-437B, Birmingham, Alabama 35294, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Allan Z Zhao azhao@pitt.edu 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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