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

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

Research output: Contribution to journalArticleScientificpeer-review

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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.

Obesity-associated insulin resistance is characterized by a state of low-grade inflammation (1) that affects adipocyte function (2) and is associated with macrophage infiltration of adipose tissue (3). Additional evidence exists that diet-induced obesity (DIO) is associated with a switch in polarization of adipose tissue macrophages (ATMs) from an anti-inflammatory (M2) to a proinflammatory (M1) state (4,5). The pathogenic relevance of this change in polarization is highlighted by the specific clustering of M1 macrophages around necrotic crown-like structures, in contrast with the randomly scattered distribution of the anti-inflammatory M2 macrophages within adipose tissue (6). Diphtheria toxin–induced death of CD11c+ cells reduces crown-like structure formation and improves insulin sensitivity (7), subsequently emphasizing the pathogenic contribution of CD11c+ M1 macrophages to the metabolic syndrome.

To explain the primary propolarizing events, we recently proposed the adipose tissue expandability hypothesis (8,9), in which the link between obesity, inflammation, and metabolic complications is directly related to the failure of adipose tissue to expand and meet storage demands (10). We proposed that the impaired ability of adipose tissue to expand further and adipose dysfunction result in lipid spillage from adipocytes, thus promoting lipid toxicity and subsequent inflammation (11–13). Although indirect evidence indicates that dysregulated lipid metabolism may alter macrophage activation (13), the mechanism through which lipids exert their metabolic effects in these cells and which specific lipid species are involved remains unclear. On the basis of the expandability hypothesis (14), we speculated that obesity-induced polarization of ATMs may be another lipotoxic manifestation of the metabolic syndrome resulting from the ectopic accumulation of lipids in ATMs.

In this study, we investigated lipid-induced toxicity as the pathogenic link between expansion of adipose tissue and ATM polarization. Specifically, we studied ATMs and adipocytes in parallel from both genetic and diet-induced murine models of obesity at different stages of the development of obesity and insulin resistance. Our results indicate that M1 polarization is associated with the accumulation of lipid species and the proliferation of lipid droplets in ATMs, which then resemble vascular foam cells. The accumulation of lipids in ATMs coincided with the induction of gene-expression networks associated with lipid uptake, storage, and metabolism. Our research also reveals qualitative changes in the lipid species that accumulate in ATMs. Finally, we provide pharmacological evidence that improving fat deposition in adipocytes promotes changes in the partitioning of lipids toward adipocytes and away from macrophages, which could prevent the proinflammatory switch of ATMs in severely obese mice.
Original languageEnglish
Pages (from-to)797-809
JournalDiabetes
Volume60
Issue number3
DOIs
Publication statusPublished - 2011
MoE publication typeA1 Journal article-refereed

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Obese Mice
Adipocytes
Adipose Tissue
Macrophages
Lipids
Obesity
Insulin Resistance
Inflammation
Foam Cells
rosiglitazone
Diet
Crowns

Cite this

Prieur, X., Mok, C. Y. L., Velagapudi, V., Núñez, V., Fuentes, L., Montaner, D., ... Vidal-Puig, A. (2011). Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. Diabetes, 60(3), 797-809. https://doi.org/10.2337/db10-0705
Prieur, Xavier ; Mok, Crystal Y.L. ; Velagapudi, Vidya ; Núñez, Vanessa ; Fuentes, Lucía ; Montaner, David ; Ishikawa, Ko ; Camacho, Alberto ; Barbarroja, Nuria ; O'Rahilly, Stephen ; Sethi, Jaswinder ; Dopazo, Joaquin ; Orešič, Matej ; Ricote, Mercedes ; Vidal-Puig, Antonio. / Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. In: Diabetes. 2011 ; Vol. 60, No. 3. pp. 797-809.
@article{0eec1901a9d443eda9c13ad92881acdc,
title = "Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice",
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.Obesity-associated insulin resistance is characterized by a state of low-grade inflammation (1) that affects adipocyte function (2) and is associated with macrophage infiltration of adipose tissue (3). Additional evidence exists that diet-induced obesity (DIO) is associated with a switch in polarization of adipose tissue macrophages (ATMs) from an anti-inflammatory (M2) to a proinflammatory (M1) state (4,5). The pathogenic relevance of this change in polarization is highlighted by the specific clustering of M1 macrophages around necrotic crown-like structures, in contrast with the randomly scattered distribution of the anti-inflammatory M2 macrophages within adipose tissue (6). Diphtheria toxin–induced death of CD11c+ cells reduces crown-like structure formation and improves insulin sensitivity (7), subsequently emphasizing the pathogenic contribution of CD11c+ M1 macrophages to the metabolic syndrome.To explain the primary propolarizing events, we recently proposed the adipose tissue expandability hypothesis (8,9), in which the link between obesity, inflammation, and metabolic complications is directly related to the failure of adipose tissue to expand and meet storage demands (10). We proposed that the impaired ability of adipose tissue to expand further and adipose dysfunction result in lipid spillage from adipocytes, thus promoting lipid toxicity and subsequent inflammation (11–13). Although indirect evidence indicates that dysregulated lipid metabolism may alter macrophage activation (13), the mechanism through which lipids exert their metabolic effects in these cells and which specific lipid species are involved remains unclear. On the basis of the expandability hypothesis (14), we speculated that obesity-induced polarization of ATMs may be another lipotoxic manifestation of the metabolic syndrome resulting from the ectopic accumulation of lipids in ATMs.In this study, we investigated lipid-induced toxicity as the pathogenic link between expansion of adipose tissue and ATM polarization. Specifically, we studied ATMs and adipocytes in parallel from both genetic and diet-induced murine models of obesity at different stages of the development of obesity and insulin resistance. Our results indicate that M1 polarization is associated with the accumulation of lipid species and the proliferation of lipid droplets in ATMs, which then resemble vascular foam cells. The accumulation of lipids in ATMs coincided with the induction of gene-expression networks associated with lipid uptake, storage, and metabolism. Our research also reveals qualitative changes in the lipid species that accumulate in ATMs. Finally, we provide pharmacological evidence that improving fat deposition in adipocytes promotes changes in the partitioning of lipids toward adipocytes and away from macrophages, which could prevent the proinflammatory switch of ATMs in severely obese mice.",
author = "Xavier Prieur and Mok, {Crystal Y.L.} and Vidya Velagapudi and Vanessa N{\'u}{\~n}ez and Luc{\'i}a Fuentes and David Montaner and Ko Ishikawa and Alberto Camacho and Nuria Barbarroja and Stephen O'Rahilly and Jaswinder Sethi and Joaquin Dopazo and Matej Orešič and Mercedes Ricote and Antonio Vidal-Puig",
year = "2011",
doi = "10.2337/db10-0705",
language = "English",
volume = "60",
pages = "797--809",
journal = "Diabetes",
issn = "0012-1797",
number = "3",

}

Prieur, X, Mok, CYL, Velagapudi, V, Núñez, V, Fuentes, L, Montaner, D, Ishikawa, K, Camacho, A, Barbarroja, N, O'Rahilly, S, Sethi, J, Dopazo, J, Orešič, M, Ricote, M & Vidal-Puig, A 2011, 'Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice', Diabetes, vol. 60, no. 3, pp. 797-809. https://doi.org/10.2337/db10-0705

Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice. / Prieur, Xavier; Mok, Crystal Y.L.; Velagapudi, Vidya; Núñez, Vanessa; Fuentes, Lucía; Montaner, David; Ishikawa, Ko; Camacho, Alberto; Barbarroja, Nuria; O'Rahilly, Stephen; Sethi, Jaswinder; Dopazo, Joaquin; Orešič, Matej; Ricote, Mercedes (Corresponding Author); Vidal-Puig, Antonio (Corresponding Author).

In: Diabetes, Vol. 60, No. 3, 2011, p. 797-809.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Differential lipid partitioning between adipocytes and tissue macrophages modulates macrophage lipotoxicity and M2/M1 polarization in obese mice

AU - Prieur, Xavier

AU - Mok, Crystal Y.L.

AU - Velagapudi, Vidya

AU - Núñez, Vanessa

AU - Fuentes, Lucía

AU - Montaner, David

AU - Ishikawa, Ko

AU - Camacho, Alberto

AU - Barbarroja, Nuria

AU - O'Rahilly, Stephen

AU - Sethi, Jaswinder

AU - Dopazo, Joaquin

AU - Orešič, Matej

AU - Ricote, Mercedes

AU - Vidal-Puig, Antonio

PY - 2011

Y1 - 2011

N2 - 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.Obesity-associated insulin resistance is characterized by a state of low-grade inflammation (1) that affects adipocyte function (2) and is associated with macrophage infiltration of adipose tissue (3). Additional evidence exists that diet-induced obesity (DIO) is associated with a switch in polarization of adipose tissue macrophages (ATMs) from an anti-inflammatory (M2) to a proinflammatory (M1) state (4,5). The pathogenic relevance of this change in polarization is highlighted by the specific clustering of M1 macrophages around necrotic crown-like structures, in contrast with the randomly scattered distribution of the anti-inflammatory M2 macrophages within adipose tissue (6). Diphtheria toxin–induced death of CD11c+ cells reduces crown-like structure formation and improves insulin sensitivity (7), subsequently emphasizing the pathogenic contribution of CD11c+ M1 macrophages to the metabolic syndrome.To explain the primary propolarizing events, we recently proposed the adipose tissue expandability hypothesis (8,9), in which the link between obesity, inflammation, and metabolic complications is directly related to the failure of adipose tissue to expand and meet storage demands (10). We proposed that the impaired ability of adipose tissue to expand further and adipose dysfunction result in lipid spillage from adipocytes, thus promoting lipid toxicity and subsequent inflammation (11–13). Although indirect evidence indicates that dysregulated lipid metabolism may alter macrophage activation (13), the mechanism through which lipids exert their metabolic effects in these cells and which specific lipid species are involved remains unclear. On the basis of the expandability hypothesis (14), we speculated that obesity-induced polarization of ATMs may be another lipotoxic manifestation of the metabolic syndrome resulting from the ectopic accumulation of lipids in ATMs.In this study, we investigated lipid-induced toxicity as the pathogenic link between expansion of adipose tissue and ATM polarization. Specifically, we studied ATMs and adipocytes in parallel from both genetic and diet-induced murine models of obesity at different stages of the development of obesity and insulin resistance. Our results indicate that M1 polarization is associated with the accumulation of lipid species and the proliferation of lipid droplets in ATMs, which then resemble vascular foam cells. The accumulation of lipids in ATMs coincided with the induction of gene-expression networks associated with lipid uptake, storage, and metabolism. Our research also reveals qualitative changes in the lipid species that accumulate in ATMs. Finally, we provide pharmacological evidence that improving fat deposition in adipocytes promotes changes in the partitioning of lipids toward adipocytes and away from macrophages, which could prevent the proinflammatory switch of ATMs in severely obese mice.

AB - 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.Obesity-associated insulin resistance is characterized by a state of low-grade inflammation (1) that affects adipocyte function (2) and is associated with macrophage infiltration of adipose tissue (3). Additional evidence exists that diet-induced obesity (DIO) is associated with a switch in polarization of adipose tissue macrophages (ATMs) from an anti-inflammatory (M2) to a proinflammatory (M1) state (4,5). The pathogenic relevance of this change in polarization is highlighted by the specific clustering of M1 macrophages around necrotic crown-like structures, in contrast with the randomly scattered distribution of the anti-inflammatory M2 macrophages within adipose tissue (6). Diphtheria toxin–induced death of CD11c+ cells reduces crown-like structure formation and improves insulin sensitivity (7), subsequently emphasizing the pathogenic contribution of CD11c+ M1 macrophages to the metabolic syndrome.To explain the primary propolarizing events, we recently proposed the adipose tissue expandability hypothesis (8,9), in which the link between obesity, inflammation, and metabolic complications is directly related to the failure of adipose tissue to expand and meet storage demands (10). We proposed that the impaired ability of adipose tissue to expand further and adipose dysfunction result in lipid spillage from adipocytes, thus promoting lipid toxicity and subsequent inflammation (11–13). Although indirect evidence indicates that dysregulated lipid metabolism may alter macrophage activation (13), the mechanism through which lipids exert their metabolic effects in these cells and which specific lipid species are involved remains unclear. On the basis of the expandability hypothesis (14), we speculated that obesity-induced polarization of ATMs may be another lipotoxic manifestation of the metabolic syndrome resulting from the ectopic accumulation of lipids in ATMs.In this study, we investigated lipid-induced toxicity as the pathogenic link between expansion of adipose tissue and ATM polarization. Specifically, we studied ATMs and adipocytes in parallel from both genetic and diet-induced murine models of obesity at different stages of the development of obesity and insulin resistance. Our results indicate that M1 polarization is associated with the accumulation of lipid species and the proliferation of lipid droplets in ATMs, which then resemble vascular foam cells. The accumulation of lipids in ATMs coincided with the induction of gene-expression networks associated with lipid uptake, storage, and metabolism. Our research also reveals qualitative changes in the lipid species that accumulate in ATMs. Finally, we provide pharmacological evidence that improving fat deposition in adipocytes promotes changes in the partitioning of lipids toward adipocytes and away from macrophages, which could prevent the proinflammatory switch of ATMs in severely obese mice.

U2 - 10.2337/db10-0705

DO - 10.2337/db10-0705

M3 - Article

VL - 60

SP - 797

EP - 809

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 3

ER -