Metabolic diseases, such as obesity and type-2 diabetes, are characterised by defective insulin signalling within neurons of the arcuate nucleus of the hypothalamus (ARC). This phenomenon termed “insulin resistance” promotes sustained food intake, hepatic glucose production and attenuates adipose thermogenesis; pathophysiological processes that collectively drive the development and maintenance of metabolic disease. The mechanisms underlying insulin resistance within the ARC are unclear.
We have identified that metabolically relevant neuronal populations within the ARC are encased by a specialised extracellular matrix, termed a perineuronal net (PNN). We report for the first time that the PNNs surrounding ARC neurons become significantly remodelled in both composition, density, and area in dietary and genetic models of obesity, pre-diabetes, and type 2 diabetes. Enzymatic digestion of the PNN specifically within the ARC of diet-induced obese mice ameliorates insulin resistance through the enhancement of circulating insulin penetrance into the ARC parenchyma. The resulting reinstatement of insulin signalling in the ARC consequently promotes weight loss and improves whole-body glycaemic control through the repression of feeding behaviour and enhanced adipose tissue thermogenesis. These effects are insulin receptor mediated as they are lost in mice specifically lacking functional insulin receptors on metabolically relevant ARC neurons encased within a PNN.
Finally, we have established a viable pharmacological approach to perturb the synthesis of ARC PNNs for the treatment of metabolic disease. We have identified that intracerebroventricular delivery of a potent chondroitin-sulphate proteoglycan inhibitor to the brains of diet-induced obese mice results in sustained beneficial effects on weight loss and glycaemic control. Our findings provide a previously undiscovered role of the PNN as a novel disease mechanism underlying neuronal insulin resistance and highlight an exciting potential therapeutic target alongside a drug candidate for the treatment of metabolic disease.