Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity.
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.


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)-1beta, -6, -8, and -10; tumor necrosis factor-alpha; 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.
Wentworth
John M
JM
Autoimmunity and Transplantation Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
Naselli
Gaetano
G
Brown
Wendy A
WA
Doyle
Lisa
L
Phipson
Belinda
B
Smyth
Gordon K
GK
Wabitsch
Martin
M
O'Brien
Paul E
PE
Harrison
Leonard C
LC
D017667:Adipocytes / Q000276:immunology / Q000378:metabolism; D000273:Adipose Tissue / Q000276:immunology* / Q000378:metabolism; D000704:Analysis of Variance; D015992:Body Mass Index; D039521:CD11c Antigen / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology* / Q000378:metabolism; D009765:Obesity / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D039521:CD11c Antigen; D007328:Insulin; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D005947:Glucose