SUN-586 CXCR2 Repression by Glucocorticoids in Adipose Tissue

Abstract

Obesity-induced type 2 diabetes (T2D) is a significant risk factor of cardiovascular disease (CVD), which affects 28.1 million adults in the United States. Adipose tissue chronic inflammation is one of the main factors that drive obesity-induced insulin resistance (IR) and T2D. Despite several studies that have shown a link between obesity, adipose tissue inflammation, and IR/T2D, the mechanisms underlying this association are not well understood. Synthetic glucocorticoids are widely used for their potent anti-inflammatory actions; however, their use is hampered due to off-target side effects. Glucocorticoids exert profound effects on adipose tissue, including the regulation of adipocyte metabolism and immune functions. However, whether their effects on adipose tissue are positive or negative it is still a controversial topic. Genome-wide microarray data obtained from adipocyte-specific glucocorticoid receptor (GR) knockout (AdipoGRKO) mice showed that lack of GR leads to a significant increase in the expression of pro-inflammatory genes in white adipose tissue (WAT). Moreover, WAT isolated from adipoGRKO mice demonstrated significant increase in immune cell infiltration, which correlates with our gene expression data. Among the most up-regulated genes, we found the C-X-C Motif Chemokine Receptor 2 (CXCR2), which is a critical mediator of chemotaxis to the sites of inflammation. Although studies have shown the presence of CXCR2 in adipocytes and suggested the contribution of CXCR2 signaling in adipocyte development, its role in obesity-driven adipose tissue inflammation is unknown. This led us to hypothesize that adipocyte specific administration of glucocorticoids can reduce obesity-induced adipocyte inflammation by inhibiting CXCR2 gene transcription and signaling. Our in vitro studies using 3T3-L1 cells derived adipocytes showed that treatment with the synthetic glucocorticoid, Dexamethasone (Dex) led to a significant repression of CXCR2 mRNA and protein levels. Correlating with these results, Dex treatment significantly inhibited macrophage migration to adipocytes in a mechanism dependent on GR activation and repression of CXCR2. Furthermore, these results were recapitulated in vivo. Together our findings suggest that local delivery of glucocorticoids to adipose tissue could ameliorate inflammation and reduce the risk of developing IR and T2D.