Role of Chemokine Receptor CXCR7 in Adipocyte Physiology and Disease
Type of DegreePhD Dissertation
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Objective—Chemokines and chemokine receptors have long been shown to play important roles in inflammation, obesity, and type II diabetes. CXCR7 is characterized as an atypical chemokine receptor whose function as a signaling or non-signaling scavenger receptor is still under debate. However, the exact role of CXCR7 in obesity and obesity-induced insulin resistance remains unknown. The aim of this study was to determine the expression and function of human visceral adipocyte CXCR7 linked to insulin resistance. Methods and results—Here we show for the first time that CXCR7 was detected in human visceral preadipocytes. Using RT-PCR and flow cytometry studies, we found that both CXCR7 mRNA and its protein expressions were significantly upregulated during the differentiation of human visceral adipocytes. Stimulation of CXCR7 by SDF-1 or LIH383 (a CXCR7-selective peptide ligand) increased lipid droplets formation during adipocytes differentiation. Activation of CXCR7 by its agonists inhibited adipolysis in mature adipocytes. In addition, we found that SDF-1 or LIH383 treatment inhibited AKT phosphorylation in a dose-dependent manner with no effect on ERK1/2 and JNK signaling pathways, which indicates a selective suppression of the AKT signaling axis by CXCR7. Furthermore, activation of CXCR7 by SDF-1 inhibited insulin signaling to the AKT pathway, insulin-induced PIP3 accumulation and glucose uptake. In contrast, ablation of CXCR7 by CRISPR/Cas9 system restored AKT signaling and enhanced insulin sensitivity in human visceral adipocytes. Conclusions—CXCR7 is upregulated during human visceral adipocyte differentiation, which is required for SDF-1 inhibition of AKT pathway, contributing to adipogenesis. In addition, CXCR7 inhibits insulin signaling to AKT pathway, thereby inhibiting insulin-induced glucose uptake, highlighting CXCR7 as a potential new drug target against obesity and type II diabetes.