Induction of Leptin Resistance Through Direct Interaction of C-reactive Protein With Leptin

Nat Med. 2006 Apr;12(4):425-32. doi: 10.1038/nm1372. Epub 2006 Apr 2.

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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Body Weight / drug effects
  • C-Reactive Protein / metabolism*
  • C-Reactive Protein / pharmacology
  • Carrier Proteins / isolation & purification
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Interleukin-6 / pharmacology
  • Leptin / blood
  • Leptin / metabolism*
  • Leptin / pharmacology
  • Mice
  • Mice, Obese
  • Mice, Transgenic
  • Precipitin Tests
  • RNA-Binding Proteins
  • Rats
  • Transgenes

Substances

  • Carrier Proteins
  • Interleukin-6
  • Leptin
  • RNA-Binding Proteins
  • SLIP1 protein, human
  • C-Reactive Protein