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

• Published in: Cell metabolism Vol. 21; no. 3; pp. 403 - 416
• Main Authors: Kraakman, Michael J., Kammoun, Helene L., Allen, Tamara L., Deswaerte, Virginie, Henstridge, Darren C., Estevez, Emma, Matthews, Vance B., Neill, Bronwyn, White, David A., Murphy, Andrew J., Peijs, Lone, Yang, Christine, Risis, Steve, Bruce, Clinton R., Du, Xiao-Jun, Bobik, Alex, Lee-Young, Robert S., Kingwell, Bronwyn A., Vasanthakumar, Ajithkumar, Shi, Wei, Kallies, Axel, Lancaster, Graeme I., Rose-John, Stefan, Febbraio, Mark A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2015
• Subjects: 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
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2015.02.006

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. [Display omitted] •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 resistance Macrophage recruitment to adipose tissue is a hallmark of obesity and can contribute to insulin resistance. Kraakman et al. show that IL-6 trans-signaling is responsible for macrophage recruitment to adipose tissue in obesity, a process that can be blocked by treatment with a soluble gp130Fc protein.