Hematopoietic-Specific DARC Deficiency Is Associated with Adipose Tissue Inflammation and Impaired Glucose Tolerance During Diet-Induced Obesity in Mice

Objective: Adipose tissue inflammation in obesity promotes insulin resistance and metabolic disease. The Duffy Antigen Receptor for Chemokines (DARC), a non-signaling receptor expressed on erythrocytes and on other cell types, modulates inflammation by regulating chemokine levels. Gene variants that affect DARC expression on erythrocytes are common in people of African descent. Here, we disrupted DARC expression in hematopoietic cells and adipocytes to determine the impact on obesity. Methods: DARC floxed mice were bred with vav1-Cre mice to disrupt DARC expression in hematopoietic cells (DARCΔhemato), and with adipoq-Cre mice to disrupt DARC expression in adipocytes (DARCΔadipo). Mice were fed a chow diet (CD) versus a high-fat diet (HFD) and studied in vivo. In vitro studies were conducted on preadipocytes isolated from wild-type (WT) and global DARC knockout mice. Results: HFD-fed DARCΔhemato mice exhibited impaired glucose tolerance compared with WT littermates, independent of weight gain. This was associated with increased adipose tissue inflammation and systemic oxidative stress. DARCΔadipo mice exhibited similar glucose tolerance but had subtle differences in adipose depot mass and adipocyte size compared with WT littermates. Deletion of DARC in preadipocytes had no impact on adipogenic differentiation or lipid accumulation in vitro. Similarly, endothelial-specific DARC KO mice also showed no differences in glucose tolerance compared with WT. Conclusions: DARC disruption in hematopoietic cells is associated with adipose tissue inflammation and alters glucose homeostasis during diet-induced obesity, accompanied by reduced circulating levels of several DARC-binding chemokines. The relevance of these findings to human DARC genetic variants and obesity-related metabolic disease warrants further investigation.