Journal article
Treatment of type 2 diabetes with the designer cytokine IC7Fc
M Findeisen, TL Allen, DC Henstridge, H Kammoun, AE Brandon, LL Baggio, KI Watt, M Pal, L Cron, E Estevez, C Yang, GM Kowalski, L O’Reilly, C Egan, E Sun, LM Thai, G Krippner, TE Adams, RS Lee, J Grötzinger Show all
Nature | NATURE PORTFOLIO | Published : 2019
Abstract
The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-c..
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Awarded by Cass Foundation
Funding Acknowledgements
This study was funded, in part, by the National Health & Medical Research Council of Australia (project grant 526606 and APP1156511 to M.A.F. and S.R.-J.; project grant APP1039502 to M.A.F.; development grant APP1039502 to M.A.F., T.E.A. and M.A.C.; principal research fellowship 445302 to M.A.F., senior principal research fellowship (SPRF) APP1021168 to M.A.F. and SPRF APP1116936 to M.A.F. This project was also funded, in part, by a CASS Foundation grant awarded to T.L.A. and M.A.F. and CIHR foundation grant 164321 to D.J.D. The project was also supported in part by the Victorian Government's OIS Program. We thank F.T. Wunderlich and C.M. Wunderlich for providing reagents to generate the ROSA26-IC7Fc mouse, as well as A. Nenci and J. Gonzales from the Monash Gene Targeting Facility. M.P. was supported by a research fellowship (DFG, PA-2459/1-1). We thank J. Scoble and L. Sparrow for their help in preparing PEGylated forms of IC7, J. Bentley for help with europium assays, X. Xiao and G. Lovrecz for mammalian cell line development and scale-up, L. Pontes-Braz for protein purification and the Burnet ImmunoMonitoring Facility for conducting the human PBMC experiments. The work of S.R.-J. was funded by the Deutsche Forschungsgemeinschaft (DFG), Bonn (grant no.: SFB841, project C1; grant no.: SFB877, project A1), and by the Cluster of Excellence 'Inflammation at Interfaces'.