Metabolic diseases, such as obesity and type-2 diabetes, are characterized by insulin resistance within the arcuate nucleus of the hypothalamus (ARC), a key brain region for maintaining metabolic homeostasis. Insulin resistance in ARC cells drives hyperphagia, increased adiposity, hyperglycaemia, and other metabolic dysfunctions. A specialised chondroitin sulphate extracellular matrix (ECM) encapsulates neuronal populations in the ARC and is pivotal in this process.
Our research identifies that during the development of metabolic diseases, the ARC ECM undergoes significant augmentation and remodelling due to hypothalamic inflammatory factors, leading to insulin resistance and metabolic dysfunction. Notably, this augmented ECM structure develops over the onset of obesity, encapsulating more agouti-related peptide (AgRP) neurons and increasing its intensity with a high-fat diet.
We report that enzymatic disassembly of the ECM within the ARC of obese mice enhances insulin access to the brain, promoting the remission of neuronal insulin resistance and improving metabolic health. This disassembly results in repressed feeding behaviour, decreased adiposity, increased adipose tissue thermogenesis, and improved glycaemic control. Further, we demonstrate the critical role of the ECM in insulin receptor signalling and metabolic regulation by ablating the insulin receptor on AgRP neurons in conjunction with ECM digestion. Additionally, we establish a viable pharmacological approach through intracerebroventricular and intranasal delivery of a small molecule competitive inhibitor, which attenuates ARC ECM expression, reduces adiposity, enhances energy expenditure, and improves glycaemic control.
Our findings reveal that ARC ECM augmentation and remodelling, termed neurofibrosis, is a fundamental mechanism underlying metabolic disease. This study highlights the ECM as a novel disease mechanism and therapeutic target for treating metabolic diseases, presenting promising avenues for future research and drug development.