Pathogenic hypothalamic extracellular matrix promotes metabolic disease

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
2 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)914-922
Number of pages9
JournalNature
Volume633
Issue number8031
Early online date18 Sept 2024
DOIs
Publication statusPublished - 26 Sept 2024

Bibliographical note

Copyright the Author(s) 2024. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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