Skeletal muscle IL‐6 and regulation of liver metabolism during high‐fat diet and exercise training

Interleukin (IL)‐6 is released from skeletal muscle (SkM) during exercise and has been shown to affect hepatic metabolism. It is, however, unknown whether SkM IL‐6 is involved in the regulation of exercise training‐induced counteraction of changes in carbohydrate and lipid metabolism in the liver in response to high‐fat diet (HFD) feeding. Male SkM‐specific IL‐6 KO (MKO) and Floxed mice were subjected to Chow diet, HFD or HFD combined with exercise training (HFD ExTr) for 16 weeks. Hepatic phosphoenolpyruvate carboxykinase (PEPCK) protein content decreased with both HFD and HFD ExTr in Floxed mice, but increased in IL‐6 MKO mice on HFD. In addition, the intrahepatic glucose concentration was in IL‐6 MKO mice higher in HFD than chow. Within HFD ExTr mice, hepatic glucose‐6‐phosphatase (G6Pase) 36 kDa protein content was higher in IL‐6 MKO than Floxed mice. Hepatic pyruvate dehydrogenase kinase (PDK) 4 and PDK2 protein content was in Floxed mice lower in HFD ExTr than Chow. In addition, hepatic ACC1‐phosphorylation was higher and ACC1 protein lower in HFD. Together this suggests that SkM IL‐6 regulates hepatic glucose metabolism, but does not seem to be of major importance for the regulation of oxidative capacity or lipogenesis in liver during HFD or HFD combined with exercise training.