病原性下丘脑细胞外基质促进代谢疾病

澳大利亚墨尔本大学Garron T. Dodd研究团队发现，病原性下丘脑细胞外基质促进代谢疾病。该项研究成果于2024年9月18日在线发表在《自然》杂志上。

研究人员探究了一种专门的硫酸软骨素蛋白聚糖细胞外基质，称为神经元周围网，它包绕在下丘脑弓状核（ARC）神经元周围。在代谢疾病中，ARC的神经元周围网变得增生和重塑，导致胰岛素抵抗和代谢功能障碍。

在肥胖小鼠中，通过酶解或小分子破坏神经元周围网，可以改善胰岛素进入大脑，逆转神经元胰岛素抵抗并改善代谢健康。该研究发现，ARC细胞外基质重塑是驱动代谢疾病的基本机制。

据悉，代谢疾病如肥胖和2型糖尿病的特征是胰岛素抵抗。ARC中的细胞对调节代谢至关重要，在代谢疾病的发展过程中变得胰岛素抵抗，但这些机制尚不完全清楚。

附：英文原文

Title: Pathogenic hypothalamic extracellular matrix promotes metabolic disease

Author: Beddows, Cait A., 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., Parker, Benjamin L., Brown, Robyn M., Moh, Edward S. X., Dodd, Garron T.

Issue&Volume: 2024-09-18

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 disease3,4,5,6,7,8, 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.

DOI: 10.1038/s41586-024-07922-y

Source: https://www.nature.com/articles/s41586-024-07922-y

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