We have previously shown that the gp130 cytokines interleukin-6 (IL-6) and ciliary neurotrophic factor (CNTF) can improve obesity and insulin resistance in both mice and humans ^1,2 .  However, due to the known inflammatory effects of IL6 and the antigenic response in some patients to the clinically used form of CNTF (Axokine), both proteins have no therapeutic utility.  In an attempt to overcome this issue, we have designed a chimeric gp130 ligand, termed IC7, where one gp130 binding site has been removed from IL6 and replaced with the LIFR binding site from CNTF. This "module swap" creates a new cytokine with CNTF-like, but IL-6R dependent activity. The resultant IC7 molecule was subsequently modified to improve its pharmacokinetic profile. Treatment of high fat fed, male, C57BL/6 mice with daily doses of modified IC7 for 7 days improved glucose tolerance, reduced fasting blood glucose and decreased hepatic gluconeogenic gene expression.  Furthermore, modified IC7 treatment increased hepatic AMPK activity and increased hepatic fatty acid oxidation.  Hepatic expression of the lipogenic regulator, SREBP1c, was reduced as were hepatic triacylglycerides.  No changes in hepatic inflammatory gene expression were detected.  Skeletal muscle from treated animals did not exhibit changes in AMPK activity or fatty acid oxidation.  Similarly, modified IC7 did not increase GLUT4 translocation to the cell membrane in skeletal muscle cell culture. In summary, modified IC7 offers a potential therapeutic treatment for high fat diet induced glucose intolerance by targeting hepatosteatosis. 

 Supported by the NHMRC Australia