Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin

Curat, Cyrile Anne; Wegner, V.; Sengenès, Coralie; Miranville, Alexandra; Tonus, Carolin; Busse, Rudi; Bouloumié, Anne

doi:10.1007/s00125-006-0173-z

Cited by 607 publications

(461 citation statements)

References 14 publications

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“…This study revealed that the human ATM is characterized by high expression of MR, CD163 and integrin avb5. Moreover, the data support the model of obesity-associated macrophage infiltration of the AT 2,3,[26][27][28] by showing that the abundance of CD14 pos MR pos ATMs correlates with the BMI. As a secondary outcome of this study, human M2 macrophages were for the first time thoroughly analyzed regarding surface protein expression thus corroborating other studies mainly investigating gene expression and/or murine cells.…”

Section: Discussionsupporting

confidence: 76%

“…11,12,16,29,30 Surface marker characteristics of ATMs are important not only for their quantification but also for their isolation to be used in in vitro experiments, for example, to investigate the cellular source of adipokines and chemokines. 27,31 So far, only CD31 and CD45 have been shown to be expressed on the surface of human CD14 pos cells derived from the AT. 26 However, CD45 is expressed on all haematopoietic cells and CD31 is expressed to a similar extent on ATMs and PBMs.…”

Section: Discussionmentioning

confidence: 99%

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Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

et al. 2007

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Objective: Obesity is associated with a chronic low-grade inflammation and an increased abundance of macrophages in adipose tissue. Adipose tissue macrophages (ATMs) are assumed to interfere with adipocyte function leading to insulin resistance, thereby contributing to the pathogenesis of type 2 diabetes mellitus. Macrophages exist in separate types of differentiation, but the nature of ATMs is largely unknown. Design and measurements: Stromal vascular cells (SVCs) and ATMs were isolated from human adipose tissues from different locations. We characterized ATMs phenotypically and functionally by flow cytometry, endocytosis assay and determination of secreted cytokines. For comparison, we used macrophages of the 'classical' (M1) and the 'alternative', anti-inflammatory (M2) type differentiated in vitro from peripheral blood monocytes. Results: Like prototypic M2 macrophages, ATMs expressed considerable amounts of mannose receptor, haemoglobin scavenger receptor CD163 and integrin avb5. The number of cells expressing these molecules correlated significantly with the donors' body mass indices (BMIs). Notably, SVCs positive for the common monocyte/macrophage marker CD14 contained a considerable fraction of blood monocytes, the abundance of which did not correlate with the BMIs, pointing to the requirement of the surface markers identified here for the identification of ATMs. ATMs showed endocytic activities similar to M2 macrophages and accordingly secreted high amounts of IL-10 and IL-1 receptor antagonist. However, basal and induced secretion of pro-inflammatory mediators TNF-a, IL-6, IL-1, MCP-1 and MIP-1a was even higher in ATMs than in proinflammatory M1 macrophages. Conclusion: ATMs comprise a particular macrophage type that is M2-like by surface marker expression, but they are competent to produce extensive amounts of inflammatory cytokines, which could considerably contribute to the development of insulin resistance.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

et al. 2007

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“…5,6 Obesity-associated adipose tissue inflammation is characterized by an increased abundance of adipose tissue macrophages in mice; 6,7 several studies have confirmed a correlation between body mass index (BMI) and adipose tissue macrophage numbers in humans particularly in the metabolically relevant visceral adipose tissue. [8][9][10][11] Therefore, adipose tissue macrophages are assumed to critically contribute to the pathogenesis of type 2 diabetes mellitus and the metabolic syndrome by driving obesity-associated chronic inflammation. In contrast, adipose tissue macrophages may also have cytoprotective anti-inflammatory properties, as identified by the expression of several markers that determine an alternatively activated, anti-inflammatory macrophage type, 12,13 for instance, the hemoglobin scavenger receptor CD163.…”

Section: Introductionmentioning

confidence: 99%

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

et al. 2009

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Objective: Insulin resistance in visceral obesity is substantially driven by adipose tissue inflammation, particularly by macrophages accumulating in obese adipose tissue. In contrast, adipose tissue macrophages express the hemoglobin scavenger receptor (CD163) and heme oxygenase-1 (gene: HMOX1) that together protect from oxidative stress. Our aim was to evaluate the expression of CD163 and HMOX1 in intra-abdominal visceral (omental) and subcutaneous adipose tissue as well as circulating soluble CD163 concentrations in human obesity and its association with adipose tissue inflammation, body fat distribution and insulin resistance. Methods: CD163, HMOX1 and CD68 mRNA expression in visceral and subcutaneous adipose tissue, serum concentration of soluble CD163 in morbidly obese patients (body mass index (BMI) 440 kg m À2 ), who underwent laparoscopic surgery for gastric banding (n ¼ 20), matched for age and sex to controls (BMIo30 kg m À2 ; n ¼ 20) was analyzed. Results: CD163 expression was highly upregulated in human adipose tissue and soluble CD163 serum concentration was elevated in obese vs lean subjects. HMOX1 was upregulated in adipose tissue by obesity as well and expressed predominantly in macrophages. Although CD163 expression strictly correlated with macrophage abundance, HMOX1 was additionally upregulated within macrophages. This upregulation was significantly lower in visceral compared with subcutaneous adipose tissue. Strikingly, relative visceral adipose tissue expression of HMOX1 negatively correlated with waist-to-hip ratio and the homeostasis model assessment of insulin resistance (both P ¼ 0.024). Conclusions: Visceral obesity is associated with defective upregulation of heme oxygenase-1 in visceral adipose tissue. A lack of this antioxidative and anti-inflammatory enzyme in visceral adipose tissue could contribute to the development of insulin resistance.

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“…Although the PBEF protein lacks a classic signal sequence for secretion, it is constitutively released and detected in conditioned medium from many cell types (12,13,(33)(34)(35)(36)(37). PBEF is detectable in serum and synovial fluid (1,6), and the levels of PBEF have been found to be increased in patients with rheumatoid arthritis, in whom it is clinically correlated with the Disease Activity Score in 28 joints and elevated C-reactive protein level (1,2,6).…”

Section: Discussionmentioning

confidence: 99%

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

Evans

Williams

Hayes

et al. 2011

Arthritis & Rheumatism

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Objective. To assess the ability of pre-B cell colony-enhancing factor (PBEF) to regulate inflammation and degradative processes in inflammatory arthritis, using the small molecule inhibitor APO866 in human fibroblasts in vitro and in murine collageninduced arthritis (CIA).Methods. Enzyme-linked immunosorbent assays were used to examine regulation of expression of metalloproteinases and chemokines in human fibroblasts. The role of PBEF was further examined using APO866 in mice with CIA, with effects on disease activity assessed using radiography, histology, in vivo imaging, and quantitative polymerase chain reaction (qPCR).Results. In vitro activation of human fibroblasts with PBEF promoted expression of matrix metalloproteinase 3 (MMP-3), CCL2, and CXCL8, an effect inhibited by APO866. In mice with CIA, early intervention with APO866 inhibited synovial inflammation, including chemokine-directed leukocyte infiltration, and reduced a systemic marker of inflammation, serum hyaluronic acid. APO866 blockade led to reduced expression of MMP-3 and MMP-13 in joint extracts and to a reduction in a systemic marker of cartilage erosion, serum cartilage oligomeric matrix protein. Radiologic images revealed that APO866 protected against bone erosion, while qPCR demonstrated inhibition of RANKL expression. In mice with established disease, APO866 reduced synovial inflammation and cartilage destruction, and halted bone erosion. In addition, APO866 reduced the activity of MMP-3, CCL2, and RANKL in vivo, and inhibited production of CCL2 and RANKL in synovial explants from arthritic mice, a result that was reversed with nicotinamide mononucleotide.Conclusion. These findings confirm PBEF to be an important regulator of inflammation, cartilage catabolism, and bone erosion, and highlight APO866 as a promising therapeutic agent for targeting PBEF activity in inflammatory arthritis.Pre-B cell colony-enhancing factor (PBEF) represents an inflammatory mediator that exerts enzymatic activities and is highly expressed within the synovial tissue and plasma of patients with rheumatoid arthritis (1,2). In this respect, PBEF acts as a nicotinamide phosphoribosyltransferase (referred to as NAMPT) that controls NAD biosynthesis by catalyzing nicotinamide with 5-phosphoribosyl-1-pyrophosphate (3-5). Conversely, exogenous PBEF is also described as an adipocytokine (referred to as visfatin), and can regulate cellular processes via activation of transcriptional events through NF-B, phosphatidylinositol 3-kinase, and MAP kinase (6-8). Several groups have shown that PBEF interacts with the insulin receptor (8-10); however, this notion remains controversial (11,12), and it may be that PBEF signals through an alternative signaling route. It is also unlikely that this signaling effect is attributable to the endotoxin that may be present in PBEF preparations, since coincubation with polymixin B shows no abrogation of PBEF signaling (6,10,13).In vitro activation of signaling pathways by PBEF has been shown to regulate the expression of metalloproteinases...

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Macrophages in human visceral adipose tissue: increased accumulation in obesity and a source of resistin and visfatin

Cited by 607 publications

References 14 publications

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthrit

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