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.