CXCL3 positively regulates adipogenic differentiation

Abstract

Chemokines are a family of cytokines inducing cell migration and inflammation. Recent reports have implicated the roles of chemokines in cell differentiation. However, little is known about the functional roles of chemokines in adipocytes. Here, we explored gene expression levels of chemokines and chemokine receptors during adipogenic differentiation. We have found that two chemokines, chemokine (C-X-C motif) ligand 3 (CXCL3) and CXCL13, as well as CXC chemokine receptor 2 (CXCR2), a CXCL3 receptor, are highly expressed in mature adipocytes. When 3T3-L1 cells and ST2 cells were induced to differentiate, both the number of lipid droplets and the expression levels of adipogenic markers were significantly promoted by the addition of CXCL3, but not CXCL13. Conversely, gene knockdown of either CXCL3 or CXCR2 by specific siRNA effectively inhibited the course of adipogenic differentiation. CXCL3 treatment of 3T3-L1 cells significantly induced the phosphorylation of ERK and c-jun N-terminal kinase (JNK). Furthermore, CXCL3-induced CCAAT-enhancer binding protein (C/EBP)β and δ expression was suppressed by both ERK and JNK-specific inhibitors. Furthermore, chromatin immunoprecipitation assay revealed functional binding of PPARγ2 within the cxcl3 promoter region. Taken together, these results have indicated that CXCL3 is a novel adipokine that facilitates adipogenesis in an autocrine and/or a paracrine manner through induction of c/ebpb and c/ebpd.

The chemokine receptor CXCR2 contributes to murine adipocyte development

“…This suggests that at around 6 wk of age adipocytes in the inguinal fat depot increase in size during transition to adulthood, a time period key to inguinal mammary gland maturation, and it is at this stage that CXCR2 may play a role in inguinal adipogenesis. This would possibly confirm findings from a previous study demonstrating a role for CXCR2 in adipogenesis at specific points of maturation …”

“…Here we present data explaining the basis for this phenotype. Specifically we show that CXCR2 KO female mice have smaller adipocytes in several different fat depots, possibly because of aberrant expression of CXCR2‐regulated adipogenesis related genes . Our findings may, at least in part, explain CXCR2 KO mouse protection from obesity‐induced insulin resistance .…”

“…qRT‐PCR was next used to investigate relative mRNA expression of PPARγ and fatty acid binding protein 4 (FABP4) in inguinal and subcutaneous adipose depots. Both of these genes play a key role in adipogenesis and have been shown, in vitro, to be transcriptionally regulated in response to CXCR2 signaling . In adult mice (8‐12 wk of age) no significant differences in expression of these genes was observed in either of these adipose depots (Fig.…”

“…Specifically we show that CXCR2 KO female mice have smaller adipocytes in several different fat depots, possibly because of aberrant expression of CXCR2-regulated adipogenesis related genes. 24 Our findings may, at least in part, explain CXCR2 KO mouse protection from obesityinduced insulin resistance. 25 Overall the results presented broaden our understanding of the role of the chemokine system in adipose tissue regulation and add to the developmental processes in which chemokines play a role.…”

“…Whereas the full range of adipogenesis related genes controlled by CXCR2 signaling, and the phase of maturation at which they function, remain to be determined, it is clear that chemokine signaling contributes to the regulation of adipogenesis. This may be in a cell/context specific manner mediated through ERK and JNK phosphorylation and by the regulation of expression of adipogenesis‐related genes such as PPARγ and FABP4.…”