Interleukin‐6 mediates exercise‐induced increase in insulin sensitivity in mice

Interleukin‐6 (IL‐6) is released from working skeletal muscle during exercise. We investigated the acute and the long‐term beneficial effects of IL‐6 on exercise‐induced glucose uptake in skeletal muscle and insulin sensitivity. The acute effect on exercise‐induced glucose uptake was measured in IL‐6‐deficient (IL‐6 −/− ) mice and wild‐type control animals using a tracer technique. There was no difference in serum disappearance of 3 [H]2‐deoxyglucose after a single bout of exercise between IL‐6 −/− and wild‐type mice (13565 ± 426 versus 14343 ± 1309 d.p.m. min ml −1 , P = 0.5). The glucose uptake rate in the extensor digitorum longus muscle was, however, lower in IL‐6 −/− compared with wild‐type mice (398 ± 44 versus 657 ± 41 nmol g −1 min −1 , P < 0.01). In a long‐term study, we monitored insulin sensitivity, serum retinol‐binding protein‐4 (RBP‐4) levels, running activity, food intake, body weight and body composition in IL‐6 −/− and wild‐type mice on a high‐fat diet (HFD), with or without access to running wheels. In sedentary IL‐6 −/− and wild‐type mice, the HFD decreased insulin sensitivity (glucose area under the concentration–time curve increased about 20% during an insulin tolerance test, P < 0.05 for both genotypes versus baseline) and led to a 30% increase in serum RBP‐4 levels ( P < 0.01 for both genotypes versus baseline). Wild‐type mice with access to running wheels were protected against these effects of the HFD and maintained their baseline insulin sensitivity and serum RBP‐4 levels. In contrast, IL‐6 −/− mice did not benefit from running to the same extent as wild‐type animals. The IL‐6 −/− mice with access to running wheels had a similar decrease in insulin sensitivity to their sedentary littermates (glucose area under the concentration–time curve during an insulin tolerance test in runners versus sedentary IL‐6 −/− HFD mice, 312 ± 14 versus 340 ± 22 mmol min l −1 , P = 0.4) and displayed a 14% increase in serum RBP‐4 compared with baseline levels ( P < 0.01). Our results indicate that endogenous IL‐6 contributes to the exercise‐induced increase in insulin sensitivity, but plays only a minor role for glucose uptake into skeletal muscle during exercise.