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 and Garron T. Dodd ()
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Cait A. Beddows: The University of Melbourne
Feiyue Shi: The University of Melbourne
Anna L. Horton: 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
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
Edward S. X. Moh: Macquarie University
Garron T. Dodd: The University of Melbourne

Nature, 2024, vol. 633, issue 8031, 914-922

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07922-y

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