Pathogenic hypothalamic extracellular matrix promotes metabolic disease
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Shi, Feiyue
Horton, Anna L
Dalal, Sagar
Zhang, Ping
Ling, Chang-Chun
Yong, V Wee
Loh, Kim
Cho, Ellie
Karagiannis, Chris
Rose, Adam J
Montgomery, Magdalene K
Gregorevic, Paul
Watt, Matthew J
Packer, Nicolle H
et al.
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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.
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Nature
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633
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8031
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© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
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Beddows, CA; Shi, F; Horton, AL; Dalal, S; Zhang, P; Ling, C-C; Yong, VW; Loh, K; Cho, E; Karagiannis, C; Rose, AJ; Montgomery, MK; Gregorevic, P; Watt, MJ; Packer, NH; Parker, BL; Brown, RM; Moh, ESX; Dodd, GT, Pathogenic hypothalamic extracellular matrix promotes metabolic disease, Nature, 2024, 633 (8031), pp. 914-922