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

doi:10.1038/s41586-024-07922-y

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

School of Natural Sciences

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

38 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 language	English
Pages (from-to)	914-922
Number of pages	9
Journal	Nature
Volume	633
Issue number	8031
Early online date	18 Sept 2024
DOIs	https://doi.org/10.1038/s41586-024-07922-y
Publication status	Published - 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.

Access to Document

10.1038/s41586-024-07922-y

Publisher version (open access)Final published version, 66.7 MBLicence: CC BY-NC-ND

Cite this

Beddows, C., Shi, F., Horton, A., Dalal, S., Zhang, P., Ling, C.-C., Yong, V. W., Loh, K., Cho, E., Karagiannis, C., Rose, A., Montgomery, M. K., Gregorevic, P., Watt, M., Packer, N. H., Parker, B. L., Brown, R. M., Moh, E., & Dodd, G. T. (2024). Pathogenic hypothalamic extracellular matrix promotes metabolic disease. Nature, 633(8031), 914-922. https://doi.org/10.1038/s41586-024-07922-y

@article{7078178e74e8415babd65e9559343b24,

title = "Pathogenic hypothalamic extracellular matrix promotes metabolic disease",

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.",

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

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.",

year = "2024",

month = sep,

day = "26",

doi = "10.1038/s41586-024-07922-y",

language = "English",

volume = "633",

pages = "914--922",

journal = "Nature",

issn = "1476-4687",

publisher = "Nature Publishing Groups",

number = "8031",

}

Beddows, C, Shi, F, Horton, A, Dalal, S, Zhang, P, Ling, C-C, Yong, VW, Loh, K, Cho, E, Karagiannis, C, Rose, A, Montgomery, MK, Gregorevic, P, Watt, M, Packer, NH, Parker, BL, Brown, RM, Moh, E & Dodd, GT 2024, 'Pathogenic hypothalamic extracellular matrix promotes metabolic disease', Nature, vol. 633, no. 8031, pp. 914-922. https://doi.org/10.1038/s41586-024-07922-y

TY - JOUR

T1 - Pathogenic hypothalamic extracellular matrix promotes metabolic disease

AU - Beddows, Cait

AU - Shi, Feiyue

AU - Horton, Anna

AU - Dalal, Sagar

AU - Zhang, Ping

AU - Ling, Chang-Chun

AU - Yong, V. Wee

AU - Loh, Kim

AU - Cho, Ellie

AU - Karagiannis, Chris

AU - Rose, Adam

AU - Montgomery, Magdalene K.

AU - Gregorevic, Paul

AU - Watt, Matthew

AU - Packer, Nicolle H.

AU - Parker, Benjamin L.

AU - Brown, Robyn M.

AU - Moh, Edward

AU - Dodd, Garron T.

N1 - 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.

PY - 2024/9/26

Y1 - 2024/9/26

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85204185164

UR - http://purl.org/au-research/grants/nhmrc/2002427

UR - https://dataportal.arc.gov.au/NCGP/Web/Grant/Grant/DP220102910

UR - http://purl.org/au-research/grants/arc/CE200100029

U2 - 10.1038/s41586-024-07922-y

DO - 10.1038/s41586-024-07922-y

M3 - Article

C2 - 39294371

SN - 1476-4687

VL - 633

SP - 914

EP - 922

JO - Nature

JF - Nature

IS - 8031

ER -

Pathogenic hypothalamic extracellular matrix promotes metabolic disease

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

NHMRC Ideas led by UoM: Reversing Neurofibrosis: A New Way to Treat Type-2 Diabetes

COESB: ARC Centre of Excellence in Synthetic Biology

Cite this

Pathogenic hypothalamic extracellular matrix promotes metabolic disease

Abstract

Bibliographical note

Access to Document

Other files and links

Fingerprint

Projects

NHMRC Ideas led by UoM: Reversing Neurofibrosis: A New Way to Treat Type-2 Diabetes

COESB: ARC Centre of Excellence in Synthetic Biology

Cite this