Interleukin‐6 deficiency causes tissue‐specific changes in signaling pathways in response to high‐fat diet and physical activity

This study was designed to investigate the role of interleukin‐6 (IL‐6) on high‐fat diet (HFD)‐induced glucose intolerance, and the response to voluntary physical activity in the prevention of insulin resistance. Six‐week‐old wild‐type (WT) and IL‐6 knockout (KO) mice with (RUN) or without (SED) access to running wheels were fed a HFD (60% from kcal) for 4 weeks. A glucose tolerance test revealed that blood glucose levels were 25–30% higher in KO RUN compared to all other groups. In WT RUN, weight gain was positively correlated with total caloric intake; however, this correlation was absent in KO RUN. In soleus muscle, there was a 2‐fold increase in SOCS3 expression in KO RUN compared to all other groups. In gastrocnemius and plantaris muscles, Akt phosphorylation was 31% higher in WT RUN compared to WT SED, but this effect of running was absent in KO mice. Additionally, there was a 2.4‐fold increase in leptin expression in KO RUN compared to KO SED in the gastrocnemius and plantaris muscles. In the liver, there was a 2‐ to 3.8‐fold increase in SOCS3 expression in KO SED compared to all other groups, and AMPKα phosphorylation was 27% higher in WT mice (both RUN and SED) compared to KO mice (both RUN and SED). This study provides new insights into the role of the IL‐6 in metabolism and energy storage, and highlights tissue‐specific changes in early signaling pathways in response to HFD for 4 weeks. The collective findings suggest that endogenous IL‐6 is important for the prevention of insulin resistance leading to type 2 diabetes.