Pathogenic hypothalamic extracellular matrix promotes metabolic disease

Cait A Beddows; Feiyue Shi; Anna L Horton; Sagar Dalal; Ping Zhang; Chang-Chun Ling; V Wee Yong; Kim Loh; Ellie Cho; Chris Karagiannis; Adam J Rose; Magdalene K Montgomery; Paul Gregorevic; Matthew J Watt; Nicolle H Packer; Benjamin L Parker; Robyn M Brown; Edward S X Moh; Garron T Dodd

doi:10.1038/s41586-024-07922-y

Pathogenic hypothalamic extracellular matrix promotes metabolic disease

Nature. 2024 Sep 18. doi: 10.1038/s41586-024-07922-y. Online ahead of print.

Authors

Cait A Beddows¹, Feiyue Shi¹, Anna L Horton^{2

3}, Sagar Dalal⁴, Ping Zhang⁵, Chang-Chun Ling⁵, V Wee Yong⁶, Kim Loh⁷, Ellie Cho⁸, Chris Karagiannis⁹, Adam J Rose¹⁰, Magdalene K Montgomery¹, Paul Gregorevic^{9

11}, Matthew J Watt¹, Nicolle H Packer⁴, Benjamin L Parker¹, Robyn M Brown^{2

3}, Edward S X Moh⁴, Garron T Dodd¹²

Affiliations

¹ Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
² Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia.
³ Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.
⁴ ARC Centre of Excellence in Synthetic Biology, School of Natural Sciences, Macquarie University, Sydney, New South Wales, Australia.
⁵ Department of Chemistry, University of Calgary, Calgary, Alberta, Canada.
⁶ Department of Clinical Neurosciences and the Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
⁷ St Vincent's Institute of Medical Research, Melbourne, Victoria, Australia.
⁸ Biological Optical Microscopy Platform, The University of Melbourne, Melbourne, Victoria, Australia.
⁹ Centre for Muscle Research, The University of Melbourne, Melbourne, Victoria, Australia.
¹⁰ Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia.
¹¹ Department of Neurology, The University of Washington School of Medicine, Seattle, Washington, USA.
¹² Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia. garron.dodd@unimelb.edu.au.

PMID: 39294371
DOI: 10.1038/s41586-024-07922-y

Abstract

Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance^1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease^3-8, but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases.