Pro-Inflammatory CD11c+CD206+ Adipose Tissue Macrophages Are Associated With Insulin Resistance in Human Obesity
TL;DR: These findings identify proinflammatory CD11c+ ATMs as markers of insulin resistance in human obesity and indicates they metabolize lipid and may initiate adaptive immune responses.
Abstract: OBJECTIVE Insulin resistance and other features of the metabolic syndrome have been causally linked to adipose tissue macrophages (ATMs) in mice with diet-induced obesity. We aimed to characterize macrophage phenotype and function in human subcutaneous and omental adipose tissue in relation to insulin resistance in obesity.
RESEARCH DESIGN AND METHODS Adipose tissue was obtained from lean and obese women undergoing bariatric surgery. Metabolic markers were measured in fasting serum and ATMs characterized by immunohistology, flow cytometry, and tissue culture studies.
RESULTS ATMs comprised CD11c+CD206+ cells in “crown” aggregates and solitary CD11c−CD206+ cells at adipocyte junctions. In obese women, CD11c+ ATM density was greater in subcutaneous than omental adipose tissue and correlated with markers of insulin resistance. CD11c+ ATMs were distinguished by high expression of integrins and antigen presentation molecules; interleukin (IL)-1β, -6, -8, and -10; tumor necrosis factor-α; and CC chemokine ligand-3, indicative of an activated, proinflammatory state. In addition, CD11c+ ATMs were enriched for mitochondria and for RNA transcripts encoding mitochondrial, proteasomal, and lysosomal proteins, fatty acid metabolism enzymes, and T-cell chemoattractants, whereas CD11c− ATMs were enriched for transcripts involved in tissue maintenance and repair. Tissue culture medium conditioned by CD11c+ ATMs, but not CD11c− ATMs or other stromovascular cells, impaired insulin-stimulated glucose uptake by human adipocytes.
CONCLUSIONS These findings identify proinflammatory CD11c+ ATMs as markers of insulin resistance in human obesity. In addition, the machinery of CD11c+ ATMs indicates they metabolize lipid and may initiate adaptive immune responses.
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TL;DR: The objectives of this review are to expose recent data supporting the role of the immune system in the pathogenesis of insulin resistance and type 2 diabetes and to examine various mechanisms underlying this relationship.
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...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]....
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...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 [34-36]....
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...The formation of clusters of macrophages around dead adipocytes in crown-like structures is a primary feature of chronic low-grade inflammation (359)....
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...…et al., 2003; Wentworth et al., 2010), each of which have been shown to play positive or negative roles in metabolic dysregulation and the development of obesity (Feuerer et al., 2009; Lumeng et al., 2007; Nishimura et al., 2009; Wentworth et al., 2010; Winer et al., 2011; Winer et al., 2009)....
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...…CD11c-expressing M1 macrophages (Fujisaka et al., 2009; Lumeng et al., 2007) often aggregate around necrotic adipocytes and produce excess proinflammatory cytokines, such as IL-6 and TNF-a, characteristic of obese adipose tissue in humans (Wentworth et al., 2010) and mice (Lumeng et al., 2007)....
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..., 2011), and macrophages (Lumeng et al., 2007; Weisberg et al., 2003; Wentworth et al., 2010), each of which have been shown to play positive or negative roles in metabolic dysregulation and the development of obesity (Feuerer et al....
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...…2009), regulatory T (Treg) cells (Feuerer et al., 2009), B cells (Winer et al., 2011), and macrophages (Lumeng et al., 2007; Weisberg et al., 2003; Wentworth et al., 2010), each of which have been shown to play positive or negative roles in metabolic dysregulation and the development of obesity…...
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..., 2010), each of which have been shown to play positive or negative roles in metabolic dysregulation and the development of obesity (Feuerer et al., 2009; Lumeng et al., 2007; Nishimura et al., 2009; Wentworth et al., 2010; Winer et al., 2011; Winer et al., 2009)....
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TL;DR: This review focuses on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines.
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...of CD11c-positive macrophages has been associated with insulin resistance in obese human individuals.(70) The mechanisms...
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References
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Harvard University1, Brigham and Women's Hospital2, University of Wisconsin-Madison3, University of California, Berkeley4, Technical University of Denmark5, Icahn School of Medicine at Mount Sinai6, Vienna University of Technology7, University of Erlangen-Nuremberg8, German Cancer Research Center9, University of Milan10, Johns Hopkins University11, University of Washington12, Scripps Research Institute13, Walter and Eliza Hall Institute of Medical Research14, University of Iowa15
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