| Literature DB >> 31554967 |
Maria Findeisen1, Tamara L Allen2, Darren C Henstridge2, Helene Kammoun2, Amanda E Brandon1,3, Laurie L Baggio4, Kevin I Watt5, Martin Pal1,6, Lena Cron1, Emma Estevez1, Christine Yang2, Greg M Kowalski2,7, Liam O'Reilly1, Casey Egan8, Emily Sun9, Le May Thai1, Guy Krippner2, Timothy E Adams10, Robert S Lee2, Joachim Grötzinger11, Christoph Garbers12, Steve Risis2, Michael J Kraakman2, Natalie A Mellet2, James Sligar1, Erica T Kimber1, Richard L Young13, Michael A Cowley14, Clinton R Bruce2,7, Peter J Meikle2, Paul A Baldock1, Paul Gregorevic5, Trevor J Biden1, Gregory J Cooney1,3, Damien J Keating9, Daniel J Drucker4, Stefan Rose-John11, Mark A Febbraio15,16,17.
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-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.Entities:
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Year: 2019 PMID： 31554967 DOI： 10.1038/s41586-019-1601-9
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962