Metabolic diseases such as obesity and Type-2 diabetes are characterised by insulin resistance. Excessive deposition and remodelling of extracellular matrix (ECM) promotes fibrosis and is an established disease mechanism underpinning insulin resistance within muscle, adipose tissue, and liver. The incidence and relevance of the ECM in the brain to the development of metabolic diseases remains unexplored. Cells within the arcuate nucleus of the hypothalamus (ARC) become insulin resistant during the progression of metabolic diseases which profoundly drives whole-body metabolic dysfunction. The mechanisms underlying insulin resistance within the ARC are unclear.
We have identified a specialised chondroitin sulphate proteoglycan ECM (CSPG-ECM), which encases metabolically relevant neuronal populations within the ARC. During the progression of metabolic diseases, abrogated CSPG-ECM turnover within the ARC promotes dysfunctional ECM deposition and remodelling, resulting in neurofibrosis. We demonstrate that neurofibrosis within the ARC causally drives metabolic diseases through the promotion of neuronal insulin resistance. Disassembly of the CSPG-ECM within the ARC of obese/pre-diabetic mice profoundly improves metabolic health through enhanced transport of insulin into the ARC, promoting the remission of neuronal insulin resistance. This identifies an unprecedented role for the ECM and the development of neurofibrosis within the ARC in the progression of obesity and Type-2 diabetes. Efforts to understand insulin resistance have yielded underwhelming therapeutic impact, potentially as research has focused on peripheral tissues, overlooking the significant actions of insulin within the brain. Utilising this novel disease mechanism, we identify a “first in its class” small molecule inhibitor targeting neurofibrosis, which substantiates a novel therapeutic strategy for treating metabolic diseases.