Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

IC7: an IL6-CNTF chimera improves obesity induced glucose intolerance (#74)

Tamara Allen 1 , Guy Krippner 1 , Tim Adams 2 , Lindsay Sparrow 2 , Judy Scoble 2 , Christine Yang 1 , Emma Estevez 1 , Helene Kammoun 1 , Darren Henstridge 1 , Michael Kraakman 1 , Kylie Goy 3 , Rosemary Ffrench 3 , Liam O'Reilly 4 , Trevor Biden 4 , Vance Matthews 5 , Stefan Rose-John 6 , Mark Febbraio 1
  1. BakerIDI Heart & Diabetes Institute, Melbourne, VIC, Australia
  2. CSIRO, Materials Science & Engineering, Parkville, Victoria, Australia
  3. Viral Immunology Laboratory, Burnet Institute, Melbourne, Victoria, Australia
  4. Garvan Institute, Sydney, New South Wales, Australia
  5. Western Australian Institute for Medical Research, Perth, Western Australia, Australia
  6. Department of Biochemistry, Christian-Albrechts-Universit├Ąt zu Kiel, Kiel, Germany

We have previously shown that the gp130 cytokines IL-6 and CNTF can improve obesity and insulin resistance1,2. Axokine, a modified form of the ciliary neurotrophic factor (CNTF), showed promise as a therapy to treat obesity, but ultimately failed in clinical trials because patients developed auto-antibodies3. In an attempt to overcome this issue, we have designed a chimeric gp130 ligand, termed IC7, where the site III binding motif of CNTF has been replaced with IL-6. This "module swap" creates a novel gp130 cytokine that signals through the IL6R, gp130 and LIFR, resulting in unique metabolic effects. Treating BALB/c mice acutely with IC7 reduced circulating IL6, TNFalpha six and 12 hours after injection. Further modification of IC7 has improved both the pharmacokinetic profile and metabolic efficacy of the peptide. Treating high fat fed C57Bl/6 mice with modified IC7 (mIC7) reduced body mass, fat mass and food intake. Fasting blood glucose levels and glucose tolerance were significantly improved in treated animals with no differences in insulin levels. In contrast to IL-64, treatment of isolated islets with mIC7 showed no effect on insulin secretion. The expression of lipogenic and gluconeogenic genes was reduced in the liver of treated mice, with no change in IL6 and TNFalpha expression. Liver fat oxidation was increased and liver TAG levels were decreased. Liver glycogen was also significantly reduced. Treatment of C2C12 myotubes with mIC7, unlike IL-61 did not stimulate GLUT4 translocation to the cell membrane. In conclusion, IC7 acts through the IL6R, gp130 and LIFR to result in signalling and biological effects distinct from its parent proteins, CNTF and IL6. IC7 appears to primarily act in the liver to reduce gluconeogenesis and lipid accumulation with no evidence of exacerbated inflammation. Therefore, IC7 has potential for treatment of high fat diet-induced glucose intolerance and hepatic steatosis.

  1. Carey, A.L., et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688-2697 (2006).
  2. Watt, M.J., et al. CNTF reverses obesity-induced insulin resistance by activating skeletal muscle AMPK. Nat Med 12, 541-548 (2006).
  3. Ettinger, M.P., et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. Jama 289, 1826-1832 (2003).
  4. Ellingsgaard, H., et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 17, 1481-1489 (2011).