Resolution of NASH and hepatic fibrosis by the GLP-1R and GCGR dual-agonist cotadutide via modulating mitochondrial function and lipogenesis

Michelle L. Boland, Rhianna C. Laker, Karly Mather, Arkadiusz Nawrocki, Stephanie Oldham, Brandon B. Boland, Hilary Lewis, James Conway, Jacqueline Naylor, Silvia Guionaud, Michael Feigh, Sanne S. Veidal, Louise Lantier, Owen P. McGuinness, Joseph Grimsby, Cristina M. Rondinone, Lutz Jermutus, Martin R. Larsen, James L. Trevaskis, Christopher J. Rhodes*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a glucagon-like protein-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist, was shown to reduce blood glycaemia, body weight and hepatic steatosis in people with type 2 diabetes mellitus. Here, we demonstrate that the effects of cotadutide in reducing body weight and food intake and improving glucose control are predominantly mediated through Glp-1 signalling, whereas its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signalling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism enzymes in liver of mice treated with cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, consistent with a unique therapeutic contribution of GCGR agonism by cotadutide in vivo. Notably, cotadutide also alleviated fibrosis to a greater extent than liraglutide or obeticholic acid, despite dose adjustment to achieve similar weight loss in two preclinical mouse models of NASH. Thus, cotadutide, via direct hepatic (GcgR) and extrahepatic (Glp-1R) effects, exerts multifactorial improvement in liver function and is a promising therapeutic option for the treatment of steatohepatitis.

Original languageEnglish
JournalNature Metabolism
Volume2
Pages (from-to)413-431
DOIs
Publication statusPublished - 2020

Fingerprint Dive into the research topics of 'Resolution of NASH and hepatic fibrosis by the GLP-1R and GCGR dual-agonist cotadutide via modulating mitochondrial function and lipogenesis'. Together they form a unique fingerprint.

  • Cite this

    Boland, M. L., Laker, R. C., Mather, K., Nawrocki, A., Oldham, S., Boland, B. B., Lewis, H., Conway, J., Naylor, J., Guionaud, S., Feigh, M., Veidal, S. S., Lantier, L., McGuinness, O. P., Grimsby, J., Rondinone, C. M., Jermutus, L., Larsen, M. R., Trevaskis, J. L., & Rhodes, C. J. (2020). Resolution of NASH and hepatic fibrosis by the GLP-1R and GCGR dual-agonist cotadutide via modulating mitochondrial function and lipogenesis. Nature Metabolism, 2, 413-431. https://doi.org/10.1038/s42255-020-0209-6