APPS November 2002 Meeting Abstract 238

The plasma concentration of the cytokine interleukin (IL)-6 increases ~100-fold during muscular exercise. Until recently the cellular origin of this increase has largely been ignored but it was commonly thought that the immune cells were responsible for the increase. Recently, however, we demonstrated that the monocytes are not the source of the exercise-induced increase in plasma IL-6 ^1,2, leading to the discovery that the IL-6 gene is present in human skeletal muscle ³, undergoes rapid transcription ⁴during contraction and results in IL-6 protein release ⁵. IL-6 has been hypothesized as the link between inflammation, obesity and coronary heart disease but given the many beneficial effects of physical exercise on health, the idea of IL-6 being detrimental is anomalous. Recently, Wallenius et al.⁶demonstrated that IL-6 deficient mice develop mature-onset obesity. In addition, we have demonstrated that IL-6 infusion into humans increases lipolysis, fat oxidation, and fatty acid re-esterification, without causing hyperlipidemia, in the absence of changes to key lipolytic hormones and/or adverse side effects ⁷. Taken together, these previous studies suggest that IL-6 provides a potential therapeutic agent in the treatment of obesity related disorders. It has been suggested that the cytokine tumor necrosis factor (TNF)-α, rather than IL-6, is the cytokine that may mediate the so called "metabolic syndrome" and that one role of IL-6 may be to down-regulate TNF-α ⁸. To examine this, we injected endotoxin intravenously into healthy humans to increase systemic TNF-α to levels characteristic of patients with type 2 diabetes. We then administered the endotoxin on two further occasions where we raised IL-6 either by having subjects perform bicycle exercise, or via IL-6 infusion at rest. The endotoxin-induced increase in TNF-α was totally attenuated in both circumstances demonstrating that physical exercise and IL-6 infusion inhibit endotoxin-induced TNF-α ⁹. Given our recent findings, we propose that IL-6 is a cytokine that is released by skeletal muscle during exercise to mobilize fat for subsequent use. In addition, we suggest that IL-6 may be a possible therapeutic agent in the treatment of obesity and obesity related disorders as well as for diseases where TNF-α is chronically elevated such as type 2 diabetes and atherosclerosis.