Pathogenic hypothalamic extracellular matrix promotes metabolic disease

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. Insulin resistance is intimately linked to extracellular matrix (ECM) remodelling in peripheral tissues, where excessive ECM deposition, a phenomenon termed fibrosis, impairs insulin action and signalling. Traditionally, fibrosis has been viewed as occurring only in peripheral tissues. However, remodelling of ECM within the brain has been observed following acute brain injury and in several neurological diseases. Recent work has identified the formation of perineuronal nets (PNNs), a unique ECM subtype, around neurons that express agouti-related peptide (AgRP) in the ARC during neuronal maturation. Given the association between fibrosis and cellular dysfunction in the periphery, ECM remodelling in the ARC could represent a previously unexplored mechanism in the pathogenesis of metabolic disease. Here we identify that during the development of metabolic disease, the ARC ECM becomes augmented and remodelled, impeding insulin penetrance and resulting in insulin resistance. By disassembling the pathogenic ECM in the ARC of obese and type 2 diabetic mice, we promote disease remission and causally implicate ARC ECM remodelling as a disease mechanism and therapeutic target in metabolic disease.

Cait A. Beddows, Feiyue Shi, Anna L. Horton, Sagar Dalal, Ping Zhang, Chang-Chun Ling, V. Wee Yong, Kim Loh, Ellie Cho, Chris 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