Journal article
Pathogenic hypothalamic extracellular matrix promotes metabolic disease
CA Beddows, F Shi, AL Horton, S Dalal, P Zhang, CC Ling, VW Yong, K Loh, E Cho, C Karagiannis, AJ Rose, MK Montgomery, P Gregorevic, MJ Watt, NH Packer, BL Parker, RM Brown, ESX Moh, GT Dodd
Nature | Springer Nature | Published : 2024
Open access
Abstract
Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance1,2. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease3–8, but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with smal..
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Awarded by University of Melbourne
Funding Acknowledgements
The authors thank B. Boztepe, A. Jobling, J. Ivanusic, S. Dodd, G. Dodd and L. Bowers for feedback on this work and reagents alongside members of the Dodd, Watt and Parker laboratories for discussions. We also thank L. Bowers for help with generating Image J macros; R. Lee-Young for help with the hyperinsulinaemic-euglycaemic clamp technique; S. McDougall for electrophysiological support; C. Goodman and H. Qian for assistance with AAV vectors generation; and J. Bhandari for genotyping. This project relied on the Melbourne Mouse Metabolic Phenotyping Platform for experiments in metabolic cages, the Biological Optical Microscopy Platform and the Melbourne Histology Platform at The University of Melbourne for microscopy and histology. This work was funded by NHMRC Grants 2022/GNT2021126, 2020/GNT2002427 and 2018/GNT1160043; Australian Research Council Grants DP220102910 and CE200100029; Diabetes Australia Grants Y23G-DodG and Y20G-DodG; The University of Melbourne Deans Innovation Award; a Baillieu Research Scholarship; a Graduate Women Victoria Scholarship; and an NHMRC Investigator Grant (APP2017070 and APP2009642).