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

摘要

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.rnRESEARCH 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.rnRESULTS-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, proinflam-matory 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 CDllc~- 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.rnCONCLUSIONS-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.