Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance

Cell Metab. 2015 Mar 3;21(3):403-16. doi: 10.1016/j.cmet.2015.02.006.

Abstract

Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Adipose Tissue / physiology
  • Animals
  • Cytokine Receptor gp130 / metabolism
  • Diet, High-Fat / adverse effects*
  • Insulin Resistance / physiology*
  • Interleukin-6 / metabolism*
  • Macrophages / metabolism*
  • Macrophages / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Interleukin-6 / metabolism
  • Signal Transduction / physiology*

Substances

  • Interleukin-6
  • Receptors, Interleukin-6
  • Cytokine Receptor gp130

Associated data

  • GEO/GSE63761