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Pathogenic hypothalamic extracellular matrix promotes metabolic disease

Author

Listed:
  • Cait A. Beddows

    (The University of Melbourne)

  • Feiyue Shi

    (The University of Melbourne)

  • Anna L. Horton

    (The University of Melbourne
    The University of Melbourne)

  • Sagar Dalal

    (Macquarie University)

  • Ping Zhang

    (University of Calgary)

  • Chang-Chun Ling

    (University of Calgary)

  • V. Wee Yong

    (University of Calgary)

  • Kim Loh

    (St Vincent’s Institute of Medical Research)

  • Ellie Cho

    (The University of Melbourne)

  • Chris Karagiannis

    (The University of Melbourne)

  • Adam J. Rose

    (Monash University)

  • Magdalene K. Montgomery

    (The University of Melbourne)

  • Paul Gregorevic

    (The University of Melbourne
    The University of Washington School of Medicine)

  • Matthew J. Watt

    (The University of Melbourne)

  • Nicolle H. Packer

    (Macquarie University)

  • Benjamin L. Parker

    (The University of Melbourne)

  • Robyn M. Brown

    (The University of Melbourne
    The University of Melbourne)

  • Edward S. X. Moh

    (Macquarie University)

  • Garron T. Dodd

    (The University of Melbourne)

Abstract

Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3–8, 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.

Suggested Citation

  • 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 Grego, 2024. "Pathogenic hypothalamic extracellular matrix promotes metabolic disease," Nature, Nature, vol. 633(8031), pages 914-922, September.
    • Handle: RePEc:nat:nature:v:633:y:2024:i:8031:d:10.1038_s41586-024-07922-y
    DOI: 10.1038/s41586-024-07922-y
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