Obesity is associated with macrophage accumulation in adipose tissue

Weisberg, Stuart P.; McCann, Daniel; Desai, Manisha; Rosenbaum, Michael; Leibel, Rudolph L.; Ferrante, Anthony W.

doi:10.1172/jci200319246

Cited by 7,518 publications

(3,009 citation statements)

References 92 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: 77%

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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: 77%

“…1 These chronic inflammatory alterations are associated with increased abundance of macrophages in adipose tissue (AT). [2][3][4] Adipose tissue macrophages (ATMs)…”

Section: Introductionmentioning

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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“…Moreover, two separate reports have shown that adipose tissue is characterised by macrophage infiltration, which could affect its normal function and inflammatory properties [33,34]. In this regard, we show that although adiposity is increased in Alox5 −/− mice from as early as 12 weeks of age, the expression of inflammatory genes in adipose tissue is lower.…”

Section: Discussionsupporting

confidence: 51%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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Aims/hypothesis We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 −/− ) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. Methods Alox5 −/− and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. Results Beginning at 12 weeks of age, Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p< 0.05). Although Alox5 −/− mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed Diabetologia (2008) that Alox5 −/− mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm 2 islet (p < 0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 −/− islets were significantly lower than in WT islets (p <0.05) and accompanied by a three-to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). Conclusions/interpretation These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.

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“…Obesity is recognized as a chronic, systemic proinflammatory state involving the same cytokines that have been implicated in OA 36. Adipose tissue in obese individuals and in animal models contains increased numbers of activated macrophages that release proinflammatory cytokines such as IL‐1β, TNF, and IL‐6 37. These elevated cytokine levels promote proinflammatory changes in adipocytes that, in turn, release additional proinflammatory mediators and adipokines to amplify the inflammatory response and act both locally on adipocytes and systemically to impair insulin action in insulin target tissues 23, 24.…”

Section: Discussionmentioning

confidence: 99%

Suppressive Effects of Insulin on Tumor Necrosis Factor–Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus

Hamada

Maynard

Schott

et al. 2016

Arthritis & Rheumatology

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ObjectiveObesity is a state of chronic inflammation that is associated with insulin resistance and type 2 diabetes mellitus (DM), as well as an increased risk of osteoarthritis (OA). This study was undertaken to define the links between obesity‐associated inflammation, insulin resistance, and OA, by testing the hypotheses that 1) tumor necrosis factor (TNF) is critical in mediating these pathologic changes in OA, and 2) insulin has direct effects on the synovial joint that are compromised by insulin resistance.MethodsThe effects of TNF and insulin on catabolic gene expression were determined in fibroblast‐like synoviocytes (FLS) isolated from human OA synovium. Synovial TNF expression and OA progression were examined in 2 mouse models, high‐fat (HF) diet–fed obese mice with type 2 DM and TNF‐knockout mice. Insulin resistance was investigated in synovium from patients with type 2 DM.ResultsInsulin receptors (IRs) were abundant in both mouse and human synovial membranes. Human OA FLS were insulin responsive, as indicated by the dose‐dependent phosphorylation of IRs and Akt. In cultures of human OA FLS with exogenous TNF, the expression and release of MMP1, MMP13, and ADAMTS4 by FLS were markedly increased, whereas after treatment with insulin, these effects were selectively inhibited by >50%. The expression of TNF and its abundance in the synovium were elevated in samples from obese mice with type 2 DM. In TNF‐knockout mice, increases in osteophyte formation and synovial hyperplasia associated with the HF diet were blunted. The synovium from OA patients with type 2 DM contained markedly more macrophages and showed elevated TNF levels as compared to the synovium from OA patients without diabetes. Moreover, insulin‐dependent phosphorylation of IRs and Akt was blunted in cultures of OA FLS from patients with type 2 DM.ConclusionTNF appears to be involved in mediating the advanced progression of OA seen in type 2 DM. While insulin plays a protective, antiinflammatory role in the synovium, insulin resistance in patients with type 2 DM may impair this protective effect and promote the progression of OA.

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Obesity is associated with macrophage accumulation in adipose tissue

Cited by 7,518 publications

References 92 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

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Suppressive Effects of Insulin on Tumor Necrosis Factor–Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus

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