Adipose Tissue Dendritic Cells Are Independent Contributors to Obesity-Induced Inflammation and Insulin Resistance.
Dynamic changes of adipose tissue leukocytes, including adipose tissue macrophage (ATM) and adipose tissue dendritic cells (ATDCs), contribute to obesity-induced inflammation and metabolic disease. However, clear discrimination between ATDC and ATM in adipose tissue has limited progress in the field of immunometabolism. In this study, we use CD64 to distinguish ATM and ATDC, and investigated the temporal and functional changes in these myeloid populations during obesity. Flow cytometry and immunostaining demonstrated that the definition of ATM as F4/80+CD11b+cells overlaps with other leukocytes and that CD45+CD64+is specific for ATM. The expression of core dendritic cell genes was enriched in CD11c+CD64-cells (ATDC), whereas core macrophage genes were enriched in CD45+CD64+cells (ATM). CD11c+CD64-ATDCs expressed MHC class II and costimulatory receptors, and had similar capacity to stimulate CD4+T cell proliferation as ATMs. ATDCs were predominantly CD11b+conventional dendritic cells and made up the bulk of CD11c+cells in adipose tissue with moderate high-fat diet exposure. Mixed chimeric experiments with Ccr2-/-mice demonstrated that high-fat diet-induced ATM accumulation from monocytes was dependent on CCR2, whereas ATDC accumulation was less CCR2 dependent. ATDC accumulation during obesity was attenuated in Ccr7-/-mice and was associated with decreased adipose tissue inflammation and insulin resistance. CD45+CD64+ATM and CD45+CD64-CD11c+ATDCs were identified in human obese adipose tissue and ATDCs were increased in s.c. adipose tissue compared with omental adipose tissue. These results support a revised strategy for unambiguous delineation of ATM and ATDC, and suggest that ATDCs are independent contributors to adipose tissue inflammation during obesity.
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.|Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do, 31151, Korea.
Kae Won
0000-0001-7512-6722
KW
Cho
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.|Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
Brian F
0000-0001-6549-4230
BF
Zamarron
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.
Lindsey A
0000-0002-1756-0325
LA
Muir
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.|Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
Kanakadurga
0000-0001-8278-3800
K
Singer
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.|Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.
Cara E
0000-0003-1581-5571
CE
Porsche
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.
Jennifer B
JB
DelProposto
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109.
Lynn
L
Geletka
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109.
Kevin A
KA
Meyer
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109.|Department of Surgery, Ann Arbor Veteran's Administration Hospital, Ann Arbor, MI 48109; and.
Robert W
0000-0002-4038-4198
RW
O'Rourke
Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI 48109; clumeng@umich.edu.|Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI 48109.|Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109.
Carey N
0000-0003-0303-6204
CN
Lumeng
D000273:Adipose Tissue / Q000276:immunology*; D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D059305:Diet, High-Fat; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D007249:Inflammation / Q000276:immunology*; D007333:Insulin Resistance; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000276:immunology*; D054390:Receptors, CCR2 / Q000235:genetics; D054400:Receptors, CCR7 / Q000235:genetics; D017452:Receptors, IgG / Q000378:metabolism
C515335:Ccr2 protein, mouse; C515371:Ccr7 protein, mouse; D054390:Receptors, CCR2; D054400:Receptors, CCR7; D017452:Receptors, IgG
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