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Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice

Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice
Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice

Objective: obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.

Research design and methods: we addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.

Results: we show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.

Conclusions:our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

0012-1797
797-809
Prieur, Xavier
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Mok, Crystal Y L
47839d33-da7d-4c6e-9405-e8eeff104d06
Velagapudi, Vidya R.
826e06bc-e573-4725-a2f1-19c3acf15f5a
Núñez, Vanessa
ee3bcd99-44c7-4084-83d0-76b0ad681c53
Fuentes, Lucía
2484efb3-ff3a-44c0-8490-57af89e221d5
Montaner, David
071de84d-180d-44ca-827d-fd25540dee72
Ishikawa, Ko
38ba3704-2222-4f1d-b0b9-4ab979471505
Camacho, Alberto
e6a3d83d-47a1-4327-998c-2b0a63969255
Barbarroja, Nuria
ad10e864-08e0-4089-84e1-a6086a2f2a69
O'Rahilly, Stephen
e5c7869f-10d1-4fdc-a564-e4907be415a3
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Dopazo, Joaquin
82e659de-9a85-4a82-91e6-fdba1c15f4eb
Orešič, Matej
0238bcc4-1f43-4432-9586-da8a4ce781a4
Ricote, Mercedes
92e98dd3-9ff7-4d02-8536-1feec2fd1b98
Vidal-Puig, Antonio
7d46d380-1b9d-40cb-90a3-72679e143036
Prieur, Xavier
28f75465-9afd-43d7-acf4-ad5700ec5943
Mok, Crystal Y L
47839d33-da7d-4c6e-9405-e8eeff104d06
Velagapudi, Vidya R.
826e06bc-e573-4725-a2f1-19c3acf15f5a
Núñez, Vanessa
ee3bcd99-44c7-4084-83d0-76b0ad681c53
Fuentes, Lucía
2484efb3-ff3a-44c0-8490-57af89e221d5
Montaner, David
071de84d-180d-44ca-827d-fd25540dee72
Ishikawa, Ko
38ba3704-2222-4f1d-b0b9-4ab979471505
Camacho, Alberto
e6a3d83d-47a1-4327-998c-2b0a63969255
Barbarroja, Nuria
ad10e864-08e0-4089-84e1-a6086a2f2a69
O'Rahilly, Stephen
e5c7869f-10d1-4fdc-a564-e4907be415a3
Sethi, Jaswinder K.
923f1a81-91e4-46cd-8853-bb4a979f5a85
Dopazo, Joaquin
82e659de-9a85-4a82-91e6-fdba1c15f4eb
Orešič, Matej
0238bcc4-1f43-4432-9586-da8a4ce781a4
Ricote, Mercedes
92e98dd3-9ff7-4d02-8536-1feec2fd1b98
Vidal-Puig, Antonio
7d46d380-1b9d-40cb-90a3-72679e143036

Prieur, Xavier, Mok, Crystal Y L, Velagapudi, Vidya R., Núñez, Vanessa, Fuentes, Lucía, Montaner, David, Ishikawa, Ko, Camacho, Alberto, Barbarroja, Nuria, O'Rahilly, Stephen, Sethi, Jaswinder K., Dopazo, Joaquin, Orešič, Matej, Ricote, Mercedes and Vidal-Puig, Antonio (2011) Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes, 60 (3), 797-809. (doi:10.2337/db10-0705).

Record type: Article

Abstract

Objective: obesity-associated insulin resistance is characterized by a state of chronic, low-grade inflammation that is associated with the accumulation of M1 proinflammatory macrophages in adipose tissue. Although different evidence explains the mechanisms linking the expansion of adipose tissue and adipose tissue macrophage (ATM) polarization, in the current study we investigated the concept of lipid-induced toxicity as the pathogenic link that could explain the trigger of this response.

Research design and methods: we addressed this question using isolated ATMs and adipocytes from genetic and diet-induced murine models of obesity. Through transcriptomic and lipidomic analysis, we created a model integrating transcript and lipid species networks simultaneously occurring in adipocytes and ATMs and their reversibility by thiazolidinedione treatment.

Results: we show that polarization of ATMs is associated with lipid accumulation and the consequent formation of foam cell-like cells in adipose tissue. Our study reveals that early stages of adipose tissue expansion are characterized by M2-polarized ATMs and that progressive lipid accumulation within ATMs heralds the M1 polarization, a macrophage phenotype associated with severe obesity and insulin resistance. Furthermore, rosiglitazone treatment, which promotes redistribution of lipids toward adipocytes and extends the M2 ATM polarization state, prevents the lipid alterations associated with M1 ATM polarization.

Conclusions:our data indicate that the M1 ATM polarization in obesity might be a macrophage-specific manifestation of a more general lipotoxic pathogenic mechanism. This indicates that strategies to optimize fat deposition and repartitioning toward adipocytes might improve insulin sensitivity by preventing ATM lipotoxicity and M1 polarization.

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Published date: March 2011

Identifiers

Local EPrints ID: 415420
URI: https://eprints.soton.ac.uk/id/eprint/415420
ISSN: 0012-1797
PURE UUID: d9f71f6e-8b3d-49ef-a1f4-9415929c88b1
ORCID for Jaswinder K. Sethi: ORCID iD orcid.org/0000-0003-4157-0475

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Date deposited: 09 Nov 2017 17:30
Last modified: 14 Mar 2019 01:25

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Contributors

Author: Xavier Prieur
Author: Crystal Y L Mok
Author: Vidya R. Velagapudi
Author: Vanessa Núñez
Author: Lucía Fuentes
Author: David Montaner
Author: Ko Ishikawa
Author: Alberto Camacho
Author: Nuria Barbarroja
Author: Stephen O'Rahilly
Author: Joaquin Dopazo
Author: Matej Orešič
Author: Mercedes Ricote
Author: Antonio Vidal-Puig

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