Defective and augmented extracellular matrix, a process termed neurofibrosis, develops around neurons within the arcuate neurons of the hypothalamus (ARC) during the progression of metabolic diseases. Once established, the defective neurofibrotic extracellular environment within the ARC promotes cellular insulin resistance resulting in significant whole-body metabolic dysfunction. Whilst the causality of ARC neurofibrosis to the development of metabolic disease has recently been established, the underlying cellular and molecular mechanisms driving the pathogenesis of neurofibrosis remain entirely unexplored.
Key proteoglycan and glycosaminoglycan components of neurofibrosis are known to be expressed by neuroglia (astrocytes, oligodendrocyte precursor cells, and microglia) indicating that the pathogenesis of neurofibrosis may originate through reactive changes in neuroglia (neurogliosis) in the ARC. We demonstrated that reactive neurogliosis within the ARC emerges following one week of exposure to a high-fat, high-sugar diet. The degree and severity of neurogliosis in the ARC positively correlates with the development of neurofibrosis within the ARC from four weeks and up to twelve weeks of high-fat, high-sugar feeding. To causally link the activity of astrocytes with the development of neurofibrosis, we chemogenetically activated ARC astrocytes in lean chow-fed mice for five days. Following five days of selective ARC astrocytes activation, we observed a marked development of neurofibrosis within the ARC which drove elevated body weight and defective energy and glucose homeostasis. Notably, the effects of ARC astrocyte activation on whole-body metabolism are mediated, at least in part, through the development of neurofibrotic ECM, as these effects are attenuated following ARC extracellular matrix digestion. In contrast, chemogenetic inhibition of ARC astrocytes in diet-induced obese mice results in the reversal of neurofibrosis, which promotes remission from diet-induced obesity. These findings define a previously unidentified mechanism by which reactive astrogliosis in the ARC drives the development of metabolic disease through the pathogenesis of neurofibrosis.