Regulatory Mechanisms for Adipose Tissue M1 and M2 Macrophages in Diet-Induced Obese Mice

Abstract

OBJECTIVETo characterize the phenotypic changes of adipose tissue macrophages (ATMs) under different conditions of insulin sensitivity.RESEARCH DESIGN AND METHODSThe number and the expressions of marker genes for M1 and M2 macrophages from mouse epididymal fat tissue were analyzed using flow cytometry after the mice had been subjected to a high-fat diet (HFD) and pioglitazone treatment.RESULTSMost of the CD11c-positive M1 macrophages and the CD206-positive M2 macrophages in the epididymal fat tissue were clearly separated using flow cytometry. The M1 and M2 macrophages exhibited completely different gene expression patterns. Not only the numbers of M1 ATMs and the expression of M1 marker genes, such as tumor necrosis factor-α and monocyte chemoattractant protein-1, but also the M1-to-M2 ratio were increased by an HFD and decreased by subsequent pioglitazone treatment, suggesting the correlation with whole-body insulin sensitivity. We also found that the increased number of M2 ATMs after an HFD was associated with the upregulated expression of interleukin (IL)-10, an anti-inflammatory Th2 cytokine, in the adipocyte fraction as well as in adipose tissue. The systemic overexpression of IL-10 by an adenovirus vector increased the expression of M2 markers in adipose tissue.CONCLUSIONSM1 and M2 ATMs constitute different subsets of macrophages. Insulin resistance is associated with both the number of M1 macrophages and the M1-to-M2 ratio. The increased expression of IL-10 after an HFD might be involved in the increased recruitment of M2 macrophages.

Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity

“…Indeed, we did not find any significant modification in the expression of the macrophage marker Emr1 mRNA between ob/ob and ob/ ob-Erk1 −/− mice. Adipose tissue macrophages consist of, at the minimum, classically activated M1 macrophages and alternatively activated M2 macrophages [31][32][33]. We found that the mRNA levels of several M1 inflammatory genes were decreased in epididymal adipose tissue while the expression of genes encoding inflammation-suppressive factors such as IL-10 was not modified.…”

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…M a n u s c r i p t 6 Macrophages can be classified into two distinct subtypes: the "classically activated macrophages" phenotype, termed M1, which secrete pro-inflammatory cytokines such as IL-1β, IL-6, TNF-α, and the "alternatively activated macrophages" phenotype, termed M2 which produce anti-inflammatory cytokines such as IL-10 [4]. While well-established in mice [34,35], the existence of distinct M1 and M2 subsets of adipose tissue macrophages has not been confirmed in human, where macrophages have rather been described as being a mix between M1 and M2 phenotypes [36]. In addition to adipose tissue macrophages infiltration, obesity causes a phenotypic switch from the M2 to M1 phenotype, correlating with insulin resistance both in mice and humans [34][35][36].…”

“…While well-established in mice [34,35], the existence of distinct M1 and M2 subsets of adipose tissue macrophages has not been confirmed in human, where macrophages have rather been described as being a mix between M1 and M2 phenotypes [36]. In addition to adipose tissue macrophages infiltration, obesity causes a phenotypic switch from the M2 to M1 phenotype, correlating with insulin resistance both in mice and humans [34][35][36]. Direct and paracrine signals issued from M1 macrophages can impair insulin signaling and adipogenesis in adipocytes whereas M2 macrophages seem to protect against obesity-induced insulin resistance [4].…”

“…Of particular interest, the number of anti-inflammatory regulatory T lymphocytes decreases with obesity in adipose tissue of both mice and humans [37,39,40] and even more in obese patients with metabolic syndrome [33]. The regulatory T lymphocytes express high amount of the antiinflammatory cytokine IL-10 which inhibit macrophage migration and induce the differentiation of M2 macrophages [35,37]. A boost in the number of these cells in obese mice can improve insulin sensitivity and reduce macrophage infiltration in adipose tissue [37].…”

Adipose tissue inflammation and ectopic lipid accumulation [Review]

“…On the other hand, peroxisome proliferatoractivated receptor γ (PPARγ) and PPARδ stimulate M2 polarization of adipose tissue macrophages and thus improve systemic insulin sensitivity [29][30][31]. Indeed, activation of PPARγ by pioglitazone, a thiazolidinedione class of insulin sensitizer, improves the unbalanced M1/M2 phenotype of adipose tissue macrophages in diet-induced obese mice [32]. Interestingly, a recent study suggests that antidiabetic effects of thiazolidinediones may be mediated, at least partly, through PPARγ in macrophages [33].…”