Energy balance and body weight are regulated by hypothalamic nuclei such as the arcuate nucleus (ARC) and influenced by signals from the periphery, such as insulin. How energy balance becomes dysregulated in metabolic disease is incompletely understood. Beddows et al. have shown that thickening of a subtype of extracellular matrix (ECM) — perineuronal nets (PNNs) — that surrounds agouti-related peptide-expressing (AgRP) neurons in the ARC promotes insulin resistance, thereby driving increased food intake and weight gain.

Similar thickening of the ECM in the periphery, known as fibrosis, impedes insulin from accessing its receptors, leading to insulin resistance. The authors investigated whether the hypothalamic insulin resistance seen in obesity was also associated with fibrosis involving PNNs. The authors used several mouse models of diet-induced obesity (DIO), one of which involved feeding the mice a high-fat, high-sugar (HFHS) diet; control mice were fed standard chow. The weight gain observed in DIO mice was accompanied by a progressive build-up of PNNs (referred to as neurofibrosis) around ARC AgRP neurons, which did not occur around POMC neurons (another key metabolically relevant hypothalamic neuron type). Moreover, PNN turnover was substantially slowed in DIO mice compared with controls, owing to reduced expression of several key ECM-degrading enzymes and increased expression of their inhibitors.