Physiological outcomes of interleukin-6 in high fat diet and voluntary physical activity

Abstract

Insulin resistance is the principle step towards the progression of type 2 diabetes, and has been linked to increased circulating levels of cytokines, leading to chronic low-grade inflammation. Specifically, in chronic disease states increased interleukin-6 (IL-6) is thought to play a critical role in the regulation of insulin resistance in peripheral tissues, and has been used as a marker of insulin resistance. There is also an endogenous up-regulation of IL-6 in response to physical activity, which has been linked to improved insulin sensitivity. This leads to the question “how can elevated IL-6 lead to the development of insulin resistance, and yet also lead to increased insulin sensitivity?” Resolving the dual role of IL-6 in regulating insulin resistance/sensitivity is critical to the development of potential therapeutic interventions. This study was designed to investigate the role of 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 after 30 minutes. In WT RUN, weight gain was positively correlated with total caloric intake; however, this correlation was absent in KO RUN, which may be attributed to impaired glycogen breakdown or increased the nuogenesis in these mice. In soleus muscle, there was a 2-fold increase in SOCS3 expression in KO RUN compared to all other groups. In gastrocnemius/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/plantaris muscles. In the liver, there was a 2-3.8-fold increase in SOCS3 expression in KO SED compared to all other groups, and AMPKa phosphorylation was 27% higher in WT mice (both RUN and SED) compared to KO mice (both RUN and SED). These findings provide new insight 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.