Hypothalamic Perineuronal Net Assembly Is Required For Sustained Diabetes Remission Induced By Fgf1

Defective glucoregulatory neurocircuit activity within the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of type 2 diabetes (T2D). In the ARC of T2D-Zucker Diabetic Fatty (ZDF) rats, we have identified significant changes in the composition and abundance of extracellular perineuronal nets (PNNs) that enmesh glucoregulatory neurocircuits. Imaging of ARC PNNs, which are comprised of the chondroitin sulfate (CS) proteoglycan aggrecan and attached CS glycosaminoglycans (GAGs), show that T2D-ZDF rats exhibit a 66.4% and 77.3% decrease in aggrecan in the medial and lateral ARC areas, respectively, compared to normoglycemic controls. Distinctive sulfation of the attached CS-GAG isomers (0S-, 4S-, 6S-, 4S6S-, 2S6S-CS) differentially influence the function of PNNs. Using LC-MS/MS, we provide the first description of hypothalamic CS-GAG sulfation patterns and show that in T2D-ZDF rats, levels of the ∆4S- isomer is increased, whereas ∆6S- and ∆2S6S-CS isomers are decreased, differences predicted to disrupt protein-GAG interactions involved in neurite outgrowth and favor tissue stiffening. To determine if ARC PNNs are targets for the antidiabetic effect of fibroblast growth factor 1 (FGF1), we performed intracerebroventricular (icv) injection of FGF1 in ZDF rats and report that both the hypothalamic CS-GAG sulfation patterns and content of ARC PNNs are normalized 24 d after treatment. Western blot analysis shows that the latter effect entails a 1.7-fold increase in aggrecan protein abundance. To assess the functional significance of ARC PNN restoration by FGF1, ZDF rats received an icv FGF1 injection followed by bilateral microinjection of either ChABC, a PNN digesting enzyme, or its vehicle control into the ARC. Our finding that the duration of sustained FGF1-induced blood glucose lowering was shortened following ARC PNN digestion (p Disclosure K.M. Alonge: Research Support; Self; Novo Nordisk Inc. Z. Mirzadeh: None. J. Scarlett: None. A. Logsdon: None. J.M. Brown: None. E. Cabrales: None. C.K. Chan: None. K. Kaiyala: None. M.A. Bentsen: None. W.A. Banks: None. M. Guttman: None. T.N. Wight: None. G.J. Morton: Research Support; Self; Novo Nordisk A/S. M.W. Schwartz: Research Support; Self; Novo Nordisk A/S. Funding National Institutes of Health (P30DK017047, F32DK122662, R01DK101997, R01DK089056, R01DK083042, K08DK114474, R01GM127579, K12NS080223, P30DK035816); Barrow Neurological Foundation (1800253005); University of Washington; Novo Nordisk (CMS431104); Novo Nordisk Foundation (NNF170C0024328, NNF10CC1016515)