Portal de Periódicos da CAPES

Blocking IL-6 trans-Signaling Prevents High-Fat Diet-Induced Adipose Tissue Macrophage Recruitment but Does Not Improve Insulin Resistance

2015; Cell Press; Volume: 21; Issue: 3 Linguagem: Inglês

10.1016/j.cmet.2015.02.006

1932-7420

Michael J. Kraakman, Hélène L. Kammoun, Tamara L. Allen, Virginie Deswaerte, Darren C. Henstridge, Emma Estévez, Vance B. Matthews, Bronwyn Neill, David A. White, Andrew Murphy, Lone Peijs, Christine Yang, Steve Risis, Clinton R. Bruce, Xiao‐Jun Du, Alex Bobik, Robert S. Lee, Bronwyn A. Kingwell, Ajithkumar Vasanthakumar, Wei Shi, Axel Kallies, Graeme I. Lancaster, Stefan Rose‐John, Mark A. Febbraio,

Lipid metabolism and disorders

Highlights•IL-6 trans-signaling recruits macrophages to adipose tissue in HFD-induced obesity•Blocking IL-6 trans-signaling with sgp130Fc prevents HFD-induced ATM accumulation•Prevention of ATM accumulation in obesity does not rescue insulin resistance•Blocking IL-6 trans-signaling does not exacerbate HFD-induced insulin resistanceSummaryInterleukin-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.Graphical abstract