Therapeutic blockade of IL-6 trans-signaling rescues adipose tissue inflammation, but not insulin resistance, in high fat fed mice. — ASN Events
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Therapeutic blockade of IL-6 trans-signaling rescues adipose tissue inflammation, but not insulin resistance, in high fat fed mice. (#149)

Michael Kraakman 1 , Tamara L Allen 1 , Brownyn Neill 1 , Helene Kammoun 1 , Christine Yang 1 , Steve Risis 1 , Clinton R Bruce 1 , Graeme I Lancaster 1 , Stefan Rose-John 2 , Mark A Febbraio 1
  1. Bakeridi, Melbourne, VIC, Australia
  2. Department of Biochemistry, Christian-Albrechts University, Kiel, Germany

Interleukin -6 (IL-6) is known to be pro-inflammatory, but these pro-inflammatory effects are mediated via “IL-6 trans-signaling”, since mice over-expressing a soluble form of the gp130 protein (sgp130Fc), which prevents IL-6 trans-signaling in vivo, are protected during an air-pouch model of local inflammation1. We sought to determine whether IL-6 trans-signaling contributes to adipose tissue inflammation and insulin resistance with nutrient overload. Sgp130Fc transgenic and control (WT) mice were fed a chow or high fat diet (HFD) for 12 weeks. White adipose tissue (WAT) inflammation, measured by several methods, including the percentage of adipocytes surrounded by macrophages (F4/80+ staining) in crown like structures and the percentage of macrophages in WAT staining positive for F4/80 and CD11c were all elevated in WT mice fed HFD. Despite the equivalent fat mass compared with WT on HFD, no such increases in WAT inflammation were observed in sgp130Fc mice. To assess whether this resulted in improved metabolic homeostasis, we performed euglycemic hyperinsulinemic clamp (EHC) experiments. The glucose infusion rate during EHC was ~2-fold higher in sgp130Fc compared with WT mice. Interestingly, this difference was entirely due to an enhanced glucose disposal rate into skeletal muscle, since the neither WAT nor hepatic insulin sensitivity was different between the genotypes. We next tested the therapeutic potential of sgp130Fc in the treatment of obesity-insulin resistance, by examining whether inflammation and insulin resistance could be rescued rather than prevented. C57Bl/6 mice were fed a HFD for 18 weeks but received a twice weekly dose of sgp130Fc or saline for the final 6 weeks of HFD. Despite the resolution of WAT inflammation with sgp130Fc treatment, HFD-induced insulin resistance was not improved at all. These data demonstrate that blocking IL-6 trans-signaling in obese mice can rescue adipose tissue inflammation without improving insulin action. Based on these pre-clinical data, we suggest that targeting adipose tissue inflammation is not a viable therapeutic strategy for the treatment of insulin resistance in obesity.

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  1. Rabe, B., Chalaris, A., May, U., Waetzig, G. H., Seegert, D., Williams, A. S., Jones, S. A., Rose-John, S. & Scheller, J. (2008) Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood, 111, 1021-8.
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