Pathogenic hypothalamic extracellular matrix promotes metabolic disease
Cait A. Beddows, Feiyue Shi, Anna Horton, Sagar Dalal, Ping Zhang, Chang‐Chun Ling, V. Wee Yong, Kim Loh, Hyun‐Jung Cho, C.S. 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, Garron T. Dodd
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. Experiments in mice show that the perineural net has a key role in metabolic disease by controlling insulin access to neurons in the arcuate nucleus of the hypothalamus.