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.
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 language | English |
|---|---|
| Pages (from-to) | 797-809 |
| Journal | Diabetes |
| Volume | 60 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - 2011 |
| MoE publication type | A1 Journal article-refereed |
