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The Role of the Duffy Antigen Receptor for Chemokines in Metabolic Disease
Author(s) -
Benson Tyler Wendorf,
Chatterjee Tapan,
Joseph Joel,
Popoola Orishebawo,
Crowe Matthew,
Yiew Nicole,
Unruh Dusten,
Weintraub Daniel,
Pillai Ajay,
Williams Jo,
Mintz James,
Stansfield Brian,
Stepp David,
Brittain Julia,
Bogdanov Vladimir,
Weintraub Neal
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.307.8
Subject(s) - adipose tissue , inflammation , chemokine , medicine , endocrinology , adipose tissue macrophages , white adipose tissue , biology , bone marrow , immunology
Inflammation in adipose tissues contributes to obesity‐related insulin resistance and metabolic disease, a problem with greater prevalence in African, Asian, and Hispanic populations. The Duffy Antigen Receptor for Chemokines (DARC) is a promiscuous non‐signaling receptor expressed primarily on erythrocytes and classically thought to modulate inflammation by binding chemokines such as MCP‐1 to buffer tissue inflammation and act as a chemokine reservoir. DARC allele variants protect against malaria and are prevalent in African, Asian, and Hispanic populations. We hypothesized that genetic deletion of DARC would augment adipose tissue inflammation and glucose intolerance in the setting of diet‐induced obesity. Eight week‐old male Wild Type (WT) and DARC−/− mice (C57BL/6 background) were maintained either on chow diet or switched to high fat diet (HFD, 60% calories from fat) for up to 24 weeks. Thereafter, metabolic phenotyping was performed, mice were subsequently euthanized, and tissues and blood were collected for analysis. Bone marrow (BM) transplants were performed by irradiating eight week old WT mice and injecting BM harvested from either DARC−/− (to eliminate BM‐derived DARC) or WT mice (control). Food intake, energy expenditure and locomotion were similar between WT and DARC−/− mice, leading to equivalent body‐weight gain and adipose tissue mass. Compared to WT mice, HFD‐fed DARC−/− mice exhibited lower plasma levels of the DARC‐bound cytokines MCP‐1, CCL11 and CXCL5, but higher adipose tissue MCP‐1 mRNA expression, more adipose tissue macrophages, and significantly larger adipocytes in the visceral adipose depots, implying enhanced adipose tissue inflammation. In addition, glucose tolerance and insulin sensitivity were significantly impaired in DARC−/− mice compared to WT mice on HFD. CD DARC−/− mice did not display increased adipose inflammation; however, they were less sensitive to insulin, exhibited larger subcutaneous adipocytes, and had higher levels of leptin mRNA and AKT phosphorylation (SER473) upon insulin stimulation when compared to WT mice. Mice reconstituted with DARC −/− BM and fed a HFD did not exhibit glucose intolerance or insulin resistance compared to mice with WT BM. Notably, we detected high levels of DARC mRNA in subcutaneous and visceral (but not brown) fat depots, and DARC protein immunoreactivity was detected in subcutaneous fat from WT but not DARC −/− mice. We conclude that loss of DARC enhances HFD‐induced adipose tissue inflammation and metabolic disease. However, the mechanism appears to be independent of its expression on erythrocytes and its classic role as a chemokine buffer‐sink. We report for the first time that DARC is expressed on adipocytes, where it may regulate insulin signaling.