We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH)¹, but whether these PNNs play a role in either the pathogenesis of type 2 diabetes (T2D) or its treatment remains unclear. Here we show that PNN abundance within the Arc is markedly reduced in the Zucker diabetic fatty (ZDF) rat model of T2D, compared with normoglycaemic rats, correlating with altered PNN-associated sulfation patterns of chondroitin sulfate glycosaminoglycans in the MBH. Each of these PNN-associated changes is reversed following a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) at a dose that induces sustained diabetes remission in male ZDF rats. Combined with previous work localizing this FGF1 effect to the Arc area^2,3,4, our finding that enzymatic digestion of Arc PNNs markedly shortens the duration of diabetes remission following icv FGF1 injection in these animals identifies these extracellular matrix structures as previously unrecognized participants in the mechanism underlying diabetes remission induced by the central action of FGF1.

我们最近发现，下丘脑内侧基底 (MBH) 的弓状核 (Arc) ¹，但这些 PNN 是否在 2 型糖尿病 (T2D) 的发病机制或其治疗中发挥作用仍不清楚。在这里，我们显示与正常血糖大鼠相比，在 T2D 的 Zucker 糖尿病脂肪 (ZDF) 大鼠模型中，弧内的 PNN 丰度显着降低，这与 MBH 中硫酸软骨素糖胺聚糖的 PNN 相关硫酸化模式改变相关。在单次脑室内 (icv) 注射成纤维细胞生长因子 1 (FGF1) 后，这些 PNN 相关变化中的每一个都会逆转，其剂量可诱导雄性 ZDF 大鼠持续缓解糖尿病。结合之前的工作，将这种 FGF1 效应定位到 Arc 区域^2,3,4，我们发现 Arc PNNs 的酶消化显着缩短了这些动物中 icv FGF1 注射后糖尿病缓解的持续时间，这将这些细胞外基质结构识别为以前未被识别的参与 FGF1 中枢作用诱导的糖尿病缓解机制的参与者。