Department of Anatomy and Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, Victoria, Australia.
Nature. 2024 Sep;633(8031):914-922. doi: 10.1038/s41586-024-07922-y. Epub 2024 Sep 18.
Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease, 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.
代谢疾病，如肥胖症和 2 型糖尿病，以胰岛素抵抗为特征。在代谢疾病的进展过程中，调节代谢的下丘脑弓状核（ARC）中的细胞会产生胰岛素抵抗，但这些机制尚不完全清楚。在这里，我们研究了一种特殊的软骨素蛋白聚糖细胞外基质，称为神经周网，它围绕着 ARC 神经元。在代谢疾病中，ARC 的神经周网会增加和重塑，导致胰岛素抵抗和代谢功能障碍。在肥胖小鼠中，无论是通过酶还是小分子破坏神经周网，都可以改善胰岛素进入大脑的通道，逆转神经元胰岛素抵抗并增强代谢健康。我们的发现确定了 ARC 细胞外基质重塑是驱动代谢疾病的基本机制。
