Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Therapeutic blockade of IL-6 trans-signaling increases adipogenesis, prevents adipose tissue inflammation and does not exacerbate liver steatosis or insulin resistance in obesity. (#140)

Michael J Kraakman 1 , Helene Kammoun 1 , Tamara L Allen 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 a cytokine causally linked to many inflammatory diseases and Tocilizumab, the first humanized IL-6 receptor-inhibiting monoclonal antibody, is currently used to treat rheumatoid arthritis (RA). While this has been a revolutionary drug, weight gain, hypercholesterolemia and hyperlipidemia are noted significant side effects (for review see 1). These side effects are unsurprising since complete blockade of IL-6 signaling results in weight gain, inflammation and hepatosteatosis (for review see 2). The inflammatory effects of IL-6 appear to be 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 from inflammation3. To test the metabolic and inflammatory effects of trans-signaling blockade in the context of obesity, we carefully phenotyped Sgp130Fc and littermate control (WT) mice by feeding them a chow or high fat diet (HFD) for 12 wk. In contrast with the IL-6 knockout mice which develop adipocyte hypertrophy, inflammation, liver damage and insulin resistance4, the Sgp130Fc mice display increased adipogenesis, and are completely refractory to HFD-induced adipose tissue macrophage accumulation. In addition, Sgp130Fc do not develop exacerbated hepatosteatosis, liver inflammation or damage compared with WT mice when fed a HFD. Moreover, in contrast with complete blockade of IL-64, blocking IL-6 trans-signaling did not result in exacerbated insulin resistance, when compared with WT mice fed a HFD. Sgp130Fc has just entered human clinical trials for the treatment of RA. Based on our pre-clinical data, we suggest that if Sgp130Fc has comparable efficacy with Tocilizumab, it may present a superior therapeutic option, because it is unlikely to result in the negative metabolic side effects seen with Tociluzumab treatment. This is important since RA is a significant risk factor for cardiovascular disease.

  1. Febbraio, M.A., Rose-John, S. & Pedersen, B.K. Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases? Clin Pharmacol Ther 87, 396-398 (2010).
  2. Febbraio, M.A. Role of interleukins in obesity: implications for metabolic disease. Trends Endocrinol Metab 25, 312-319 (2014).
  3. Rabe, B., et al. Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood 111, 1021-1028 (2008).
  4. Matthews, V.B., et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53, 2431-2441 (2010).