Martin Whitham: "Proteomic exploration of inter-tissue communication during exercise" and Mark.A. Febbraio: "IC7: a novel therapy for the treatment of metabolic disease"

Friday 26 May 2017, 1.00PM

Speaker: Martin Whitham & Mark.A. Febbraio, Sydney, Australia

Martin Whitham: Myokine Biology, Cellular & Molecular Metabolism Laboratory, Garvan Institute of Medical Research, Sydney, Australia 

"Proteomic exploration of inter-tissue communication during exercise"

Exercise capacity is a powerful predictor of mortality and physical activity is known to help prevent a wide range of non-communicable diseases. That these benefits might be, in part mediated by secreted proteins is an attractive hypothesis, since it raises the possibility that such products might be manipulated for therapeutic gain. Several myokines, peptides or proteins expressed and released from skeletal muscle, have been identified. Furthermore, the liver, adipose, brain and bone are also known to secrete proteins during exercise. However, further discovery is challenging and unbiased, ‘omic’ approaches are hampered by considerable technical hurdles such as large dynamic ranges of protein abundance in tissues and plasma. We have carried out a series of quantitative proteomic screens on skeletal muscle and plasma in exercise contexts, identifying a selection of novel proteins potentially contributing to the influence of exercise on metabolic disease and cancer. In particular, we demonstrate that large numbers of proteins, not thought to circulate during exercise, do so packaged in extracellular vesicles such as exosomes. This highlights an intriguing pathway by which exercise can exert multiple biological effects. ‌ 

Mark.A. Febbraio: Cellular and Molecular Metabolism Laboratory, Division of Diabetes & Metabolism, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

"IC7: a novel therapy for the treatment of metabolic disease"

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. In a series of experiments, we have shown that IC7 has similar positive metabolic effects as CNTF, but may overcome the negative effects experienced by Axokine. Specifically, IC7 significantly improved glucose tolerance and hyperglycemia and prevents weight gain and liver steatosis in obese mice. In addition, we have shown efficacy and safety in a study in non-human primates (Macaca fascicularis). In addition, in comprehensive human cell based assays, we have demonstrated that IC7, unlike Axokine, results in no signs of immunogenicity. Thus, IC7 is a realistic and viable next generation biological for the treatment of obesity and T2D, disorders that are currently pandemic. 

Supported by the NHMRC Australia

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).

The host for these seminars is Professor Antal Rot 

Location: K/018

Email: cii@york.ac.uk

Telephone: 01904 328845