Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6-dependent pathway

Cell Metab. 2011 Apr 6;13(4):401-412. doi: 10.1016/j.cmet.2011.02.010.


Insulin resistance is often associated with impeded insulin signaling due either to decreased concentrations or functional modifications of crucial signaling molecules including insulin receptor substrates (IRS) in the liver. Many actions of adiponectin, a well-recognized antidiabetic adipokine, are currently attributed to the activation of two critical molecules downstream of AdipoR1 and R2: AMP-activated kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). However, the direct effects of adiponectin on insulin signaling molecules remain poorly understood. We show here that adiponectin upregulates IRS-2 through activation of signal transducer and activator of transcription-3 (STAT3). Surprisingly, this activation is associated with IL-6 production from macrophages induced by adiponectin through NFκB activation independent of its authentic receptors, AdipoR1 and AdipoR2. These data have unraveled an insulin-sensitizing action initiated by adiponectin leading to upregulation of hepatic IRS-2 via an IL-6 dependent pathway through a still unidentified adiponectin receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin / deficiency
  • Adiponectin / genetics
  • Adiponectin / metabolism*
  • Animals
  • Disease Models, Animal
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism*
  • Insulin Resistance
  • Interleukin-6 / deficiency
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Liver / metabolism*
  • Macrophages / metabolism*
  • Mice
  • Mice, Obese
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic
  • Receptors, Adiponectin / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction


  • Adiponectin
  • Insulin Receptor Substrate Proteins
  • Interleukin-6
  • NF-kappa B
  • Receptors, Adiponectin
  • STAT3 Transcription Factor
  • adiponectin receptor 1, mouse
  • adiponectin receptor 2, mouse