Pro-Inflammatory CD11c+CD206+ Adipose Tissue Macrophages Are Associated With Insulin Resistance in Human Obesity

Abstract

OBJECTIVEInsulin 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 METHODSAdipose 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.RESULTSATMs 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.CONCLUSIONSThese 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.

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

“…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].…”

“…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].…”

The maternal and fetal impacts of obesity and gestational diabetes on pregnancy outcome

“…These macrophages surround and engulf elements of apoptotic adipocytes and consequently contain high quantities of intracellular fat. 72,73 During pregnancy, serum markers of inflammation are raised in overweight and obese women. 74 Placental tissue examined postpartum from obese mothers also has a higher macrophage population and greater concentrations of pro-inflammatory cytokines.…”

“…Dysregulated lipid turnover and abnormal fatty acid flux can act independently in contributing to the chronic pro-inflammatory profile of obesity. 72 Elements of the intracellular inflammatory signalling pathway are stimulated directly by raised intracellular concentrations of saturated fatty acids. Upstream along this pathway, abnormal circulating concentrations of saturated fatty acids also bind and activate immune pattern recognition receptors (toll-like receptors), for which bacterial lipopolysaccharide (LPS) is the usual ligand (see Herrera chapter).…”

Association of Adipose Tissue Inflammation With Histologic Severity of Nonalcoholic Fatty Liver Disease

“…30 This subpopulation is capable of metabolizing lipids released by necrotic adipocytes and initiating adaptive immune responses. 30 In our study using immunofluorescence we confirmed the presence of increased numbers of ATMs in all histologic subgroups compared with lean controls. We showed that the number of ATMs and crownlike structures did not differ between the histologic subgroups.…”