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Journal Article
Pathogenic hypothalamic extracellular matrix promotes metabolic disease
2024
Overview
Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance
1
,
2
. Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease
3
–
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 small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases.
Experiments in mice show that the perineural net has a key role in metabolic disease by controlling insulin access to neurons in the arcuate nucleus of the hypothalamus.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 45/77
/ 64/110
/ 64/60
/ 82/29
/ 82/51
/ 9/74
/ 96/63
/ Animals
/ Arcuate Nucleus of Hypothalamus - drug effects
/ Arcuate Nucleus of Hypothalamus - metabolism
/ Arcuate Nucleus of Hypothalamus - pathology
/ Brain
/ Chondroitin Sulfate Proteoglycans - metabolism
/ Diabetes mellitus (non-insulin dependent)
/ Diet
/ Disease
/ Extracellular Matrix - drug effects
/ Extracellular Matrix - metabolism
/ Extracellular Matrix - pathology
/ Humanities and Social Sciences
/ Insulin
/ Male
/ Metabolic Diseases - metabolism
/ Metabolic Diseases - pathology
/ Metabolic Diseases - therapy
/ Mice
/ Neurons
/ Obesity
/ Rats
/ Science
/ Sulfates
