Role of IL-6 trans-signalling in obesity induced insulin resistance and metabolic disease

Interleukin (IL)-6 is an immuno-modulatory cytokine dysregulated in obesity and implicated in the development of insulin resistance. Recently, the pro-inflammatory actions of IL-6 have been found to be mediated via a soluble IL-6 receptor (sIL-6R), termed trans-signalling. Here we report that components of IL-6 trans-signalling are altered in obese patients with type 2 diabetes and that plasma sIL-6R levels are associated with markers of adiposity, insulin resistance and adipose tissue macrophage content. In vitro studies revealed a novel role for IL-6 trans-signalling in macrophage chemotaxis. We then blocked IL-6 trans-signalling in transgenic mice that over-express a human soluble glycoprotein 130-Fc (sgp130Fc) fusion protein which specifically antagonizes IL-6 trans-signalling. These mice have reduced adipose tissue macrophage content despite exacerbated fat mass. Therapeutic administration of sgp130Fc, despite reducing adipose tissue macrophages, did not improve insulin sensitivity measured by euglycemic-hyperinsulinemic clamp (EHC) studies. These data demonstrate that blocking IL-6 trans-signalling in obese mice can rescue WAT inflammation, which fails to impact systemic insulin action. Based on these data, we suggest that targeting adipose tissue inflammation is not a viable therapeutic strategy for the treatment of insulin resistance in obesity.