Hypothalamic perineuronal net assembly is required for sustained diabetes remission induced by fibroblast growth factor 1 in rats

Kimberly M. Alonge, Zaman Mirzadeh, Jarrad M. Scarlett, Aric F. Logsdon, Jenny M. Brown, Elaine Cabrales, Christina K. Chan, Karl J. Kaiyala, Marie A. Bentsen, William A. Banks, Miklos Guttman, Thomas N. Wight, Gregory J. Morton, Michael W. Schwartz*

*Corresponding author for this work

Research output: Contribution to journalLetterResearchpeer-review

28 Citations (Scopus)

Abstract

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(2-4), 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.

Original languageEnglish
JournalNature Metabolism
Volume2
Issue number10
Pages (from-to)1025-1033
Number of pages11
ISSN2522-5812
DOIs
Publication statusPublished - 2020

Keywords

  • CHONDROITIN SULFATE D
  • LIQUID-CHROMATOGRAPHY
  • EXTRACELLULAR-MATRIX
  • PREFRONTAL CORTEX
  • AXON-GROWTH
  • NEURONS
  • LEPTIN
  • PLASTICITY
  • INJECTION
  • CARTILAGE

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