Assembly of Hypothalamic Perineuronal Nets Contributes to Sustained Blood Glucose Lowering by FGF1 Action in the Brain

Abstract

The mediobasal hypothalamus (MBH) plays a key role in the homeostatic control of blood glucose levels, and defective activity of glucoregulatory neurocircuits in this brain area is implicated in the pathogenesis of type 2 diabetes mellitus (T2DM). We have identified irregularities in the abundance of perineuronal nets (PNNs), specialized extracellular matrix (ECM) lattices that regulate neurocircuit network interactions, surrounding MBH neurons in rodent models of T2DM. Specifically, diabetic Zucker Diabetic Fatty (ZDF) rats exhibit a 56% decrease in aggrecan+ PNN structures in the MBH compared to age‐matched normoglycemic WT controls, suggestive of destabilized glucose‐sensing neurocircuit interactions. To determine whether this effect is associated with changes in the relative abundance of chondroitin sulfate (CS)‐glycosaminoglycan (GAG) isomers (Δ0S‐, Δ4S‐, Δ6S‐, Δ4S6S, Δ2S6S‐CS), which constitute the glycan component of PNNs and influence the function of these matrices, we characterized CS‐GAG sulfation patterns using state‐of‐the‐art LC‐MS/MS + MRM analysis. Here, we report that diabetic ZDF rats exhibit a significant increase in Δ4S‐CS and corresponding decrease in Δ6S‐ and Δ2S6S‐CS isomers within the MBH that are suggestive of altered protein‐GAG interactions, axonal repulsion and ECM stiffening. We next sought to determine if these PNNs are targets for the effect of fibroblast growth factor 1 (FGF1) to induce sustained blood glucose lowering in ZDF rats following intracerebroventricular (icv) administration. We found that in ZDF rats, icv FGF1 injection normalized CS‐GAG composition while inducing a 2.2‐fold increase in aggrecan+ PNN structures. To determine whether this response is required for blood glucose lowering induced by central FGF1 treatment, ZDF rats received an icv injection of FGF1 followed immediately by bilateral microinjection of either vehicle or the CS‐GAG digesting enzyme, Chondroitinase ABC (ChABC), directed to the MBH to disassemble PNNs. Our finding that the duration of blood glucose lowering induced by icv FGF1 injection was markedly shortened by digestion of hypothalamic PNNs identifies PNNs as key targets for the action of FGF1 to induce sustained remission of diabetes. These data identify a key role for MBH PNNs in glucoregulatory neural network interactions involved in the homeostatic control of blood glucose.Support or Funding InformationThis project was supported by the National Institutes of Health Awards DK12266201 (to K.M.A) and DK083042 (to M.W.S). Research support also provided by Novo Nordisk, Inc (CMS‐431104).