Pathogenic hypothalamic extracellular matrix promotes metabolic disease
成果类型：
Article
署名作者：
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.
署名单位：
University of Melbourne; University of Melbourne; University of Melbourne; Florey Institute of Neuroscience & Mental Health; Macquarie University; ARC Centre of Excellence in Synthetic Biology; University of Calgary; University of Calgary; University of Calgary; St. Vincent's Institute of Medical Research; University of Melbourne; University of Melbourne; Monash University; University of Washington; University of Washington Seattle
刊物名称：
Nature
ISSN/ISSBN：
0028-6440
DOI：
10.1038/s41586-024-07922-y
发表日期：
2024-09-26
页码：
914-+
关键词：
integrin-linked kinase
chondroitin sulfate proteoglycans
insulin-resistance
long-term
muscle
inflammation
neurons
leptin
sensitivity
expression
摘要：
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.