Biphasic remodeling of arcuate nucleus perineuronal nets in diet-induced obese mice

The hypothalamic arcuate nucleus (ARC) contains neuronal populations crucial to the regulation of energy and glucose homeostasis. Many of these neurons are enmeshed by specialized extracellular matrix structures known as perineuronal nets (PNNs) that are comprised of chondroitin sulfate proteoglycans, including aggrecan (ACAN), and attached chondroitin sulfate-glycosaminoglycans. In mice, the effect of high-fat diet (HFD) to increase the abundance of ARC PNNs has been implicated in obesity- and diabetes-associated metabolic impairments. However, neither the biochemical nature nor the time course of these HFD-induced PNN changes is known. In this current work, we report that the response of ARC PNNs to HFD feeding is biphasic, characterized by a steady increase in abundance during the first ∼3 months, followed by a gradual decrease at later time points, as diet-induced obesity (DIO) becomes more fully established. Our findings suggest that this novel, biphasic patten of PNN remodeling is 1) driven by weight gain rather than by HFD composition per se, 2) specific to the hypothalamic ARC region, and 3) parallels obesity-associated changes in the circulating glucose level. Furthermore, histochemical analysis reveals that the early increase of ARC PNNs is due primarily to changes in CS glycan attachments rather than the underlying proteoglycan core protein, while long-term HFD associates with reductions of both CS glycans and ACAN. This biphasic remodeling process becomes detectable with the onset of excess weight gain and is paralleled by obesity-associated changes in glycemia. Based on these findings, we conclude that in response to HFD feeding, ARC PNNs exhibit a degree of plasticity not seen in other brain areas and that dynamic PNN remodeling associates with changes in peripheral glycemia.