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 concentrationtime 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.