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

Kimberly M. Alonge, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Zaman Mirzadeh, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.
Jarrad M. Scarlett, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Aric F. Logsdon, Department of Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA, USA.
Jenny M. Brown, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Elaine Cabrales, Department of Neurosurgery, Barrow Neurological Institute, Phoenix, AZ, USA.
Christina K. Chan, Matrix Biology Program, Benaroya Research Institute, Seattle, WA, USA.
Karl J. Kaiyala, Department of Oral Health Sciences, School of Dentistry, University of Washington, Seattle, WA, USA.
Marie A. Bentsen, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
William A. Banks, Department of Geriatric Research Education and Clinical Center (GRECC), Veterans Affairs Puget Sound Health Care System, University of Washington, Seattle, WA, USA.
Miklos Guttman, Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA.
Thomas N. Wight, Matrix Biology Program, Benaroya Research Institute, Seattle, WA, USA.
Gregory J. Morton, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA.
Michael W. Schwartz, University of Washington Medicine Diabetes Institute, University of Washington, Seattle, WA, USA. mschwart@uw.edu.

Document Type

Article

Abstract

We recently showed that perineuronal nets (PNNs) enmesh glucoregulatory neurons in the arcuate nucleus (Arc) of the mediobasal hypothalamus (MBH), 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, 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.

Medical Subject Headings

Aged; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental (drug therapy, physiopathology); Diabetes Mellitus, Type 1 (drug therapy); Diabetes Mellitus, Type 2 (drug therapy); Eating; Extracellular Matrix; Fibroblast Growth Factor 1 (administration & dosage, therapeutic use); Humans; Hypothalamus (physiopathology); Injections, Intraventricular; Male; Middle Aged; Neurons; Rats; Rats, Wistar; Rats, Zucker; Young Adult

Publication Date

10-1-2020

Publication Title

Nature metabolism

E-ISSN

2522-5812

Volume

2

Issue

10

First Page

1025

Last Page

1033

PubMed ID

32895577

Digital Object Identifier (DOI)

10.1038/s42255-020-00275-6

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