Role of interleukin-6 in states of metabolic health and disease

Obesity and type 2 diabetes are the most prevalent metabolic diseases affecting over 50% of people in the western world. Although the pathogenesis of type 2 diabetes is not fully understood, growing evidence links this disease to a state of chronic inflammation, which occurs in metabolically active tissue such as the liver, adipose tissue and skeletal muscle and results in the secretion of inflammatory cytokines, of which interleukin-6 (IL-6) is one. It is generally accepted that elevations in the plasma and/or tissue of this family of cytokines have a negative effect on whole body glucose homeostasis. While there is compelling evidence for the negative effects of resistin and TNF-á on insulin sensitivity, the role of IL-6 in the etiology of insulin resistance is not fully understood. The notion of negative effects of IL-6 in metabolic processes is further confounded by the marked elevations of IL-6 which occur in conjunction with the beneficial activity of exercise. We firstly sought to examine the effect of the lipolytic hormone adrenaline on IL-6 expression and release in order to establish whether IL-6 acts independently of adrenaline in the regulation of fat metabolism. Reporting the absence of an effect of adrenaline on IL-6, we then investigated the role of IL-6 on metabolic processes in humans at rest and during exercise in circumstances where lipolysis was inhibited. Marked increases in IL-6 circulating protein and tissue gene expression were observed with exercise and further so with fatty acid suppression. In a mouse model of IL-6 depletion marked insulin sensitivity was observed, which was reversed with IL-6 treatment. In a mouse model with normal endogenous IL-6 levels IL-6 treatment also impaired glucose tolerance. Contrastingly, in a rat model both chronic and acute IL-6 treatment improved glucose tolerance. <br><br>In summary, studies from this thesis suggest that, rather than being causally related to insulin resistance, the cytokine IL-6 increases lipolysis, fat oxidation, and glucose metabolism in insulin sensitive tissues in humans. This does not appear to be the case in the mouse, where contrasting actions are observed, perhaps due to differences in the reliance of various parameters for metabolic processes between the species.