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Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain

Obesity significantly increases the risk of developing neurodegenerative disorders, yet the precise mechanisms underlying this connection remain unclear. Defects in glial phagocytic function are a key feature of neurodegenerative disorders, as delayed clearance of neuronal debris can result in infla...

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Autores principales: Alassaf, Mroj, Rajan, Akhila
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629620/
https://www.ncbi.nlm.nih.gov/pubmed/37934726
http://dx.doi.org/10.1371/journal.pbio.3002359
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author Alassaf, Mroj
Rajan, Akhila
author_facet Alassaf, Mroj
Rajan, Akhila
author_sort Alassaf, Mroj
collection PubMed
description Obesity significantly increases the risk of developing neurodegenerative disorders, yet the precise mechanisms underlying this connection remain unclear. Defects in glial phagocytic function are a key feature of neurodegenerative disorders, as delayed clearance of neuronal debris can result in inflammation, neuronal death, and poor nervous system recovery. Mounting evidence indicates that glial function can affect feeding behavior, weight, and systemic metabolism, suggesting that diet may play a role in regulating glial function. While it is appreciated that glial cells are insulin sensitive, whether obesogenic diets can induce glial insulin resistance and thereby impair glial phagocytic function remains unknown. Here, using a Drosophila model, we show that a chronic obesogenic diet induces glial insulin resistance and impairs the clearance of neuronal debris. Specifically, obesogenic diet exposure down-regulates the basal and injury-induced expression of the glia-associated phagocytic receptor, Draper. Constitutive activation of systemic insulin release from Drosophila insulin-producing cells (IPCs) mimics the effect of diet-induced obesity on glial Draper expression. In contrast, genetically attenuating systemic insulin release from the IPCs rescues diet-induced glial insulin resistance and Draper expression. Significantly, we show that genetically stimulating phosphoinositide 3-kinase (Pi3k), a downstream effector of insulin receptor (IR) signaling, rescues high-sugar diet (HSD)-induced glial defects. Hence, we establish that obesogenic diets impair glial phagocytic function and delays the clearance of neuronal debris.
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spelling pubmed-106296202023-11-08 Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain Alassaf, Mroj Rajan, Akhila PLoS Biol Short Reports Obesity significantly increases the risk of developing neurodegenerative disorders, yet the precise mechanisms underlying this connection remain unclear. Defects in glial phagocytic function are a key feature of neurodegenerative disorders, as delayed clearance of neuronal debris can result in inflammation, neuronal death, and poor nervous system recovery. Mounting evidence indicates that glial function can affect feeding behavior, weight, and systemic metabolism, suggesting that diet may play a role in regulating glial function. While it is appreciated that glial cells are insulin sensitive, whether obesogenic diets can induce glial insulin resistance and thereby impair glial phagocytic function remains unknown. Here, using a Drosophila model, we show that a chronic obesogenic diet induces glial insulin resistance and impairs the clearance of neuronal debris. Specifically, obesogenic diet exposure down-regulates the basal and injury-induced expression of the glia-associated phagocytic receptor, Draper. Constitutive activation of systemic insulin release from Drosophila insulin-producing cells (IPCs) mimics the effect of diet-induced obesity on glial Draper expression. In contrast, genetically attenuating systemic insulin release from the IPCs rescues diet-induced glial insulin resistance and Draper expression. Significantly, we show that genetically stimulating phosphoinositide 3-kinase (Pi3k), a downstream effector of insulin receptor (IR) signaling, rescues high-sugar diet (HSD)-induced glial defects. Hence, we establish that obesogenic diets impair glial phagocytic function and delays the clearance of neuronal debris. Public Library of Science 2023-11-07 /pmc/articles/PMC10629620/ /pubmed/37934726 http://dx.doi.org/10.1371/journal.pbio.3002359 Text en © 2023 Alassaf, Rajan https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Short Reports
Alassaf, Mroj
Rajan, Akhila
Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain
title Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain
title_full Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain
title_fullStr Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain
title_full_unstemmed Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain
title_short Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain
title_sort diet-induced glial insulin resistance impairs the clearance of neuronal debris in drosophila brain
topic Short Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629620/
https://www.ncbi.nlm.nih.gov/pubmed/37934726
http://dx.doi.org/10.1371/journal.pbio.3002359
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