regulation of chemokine and chemokine receptor expression by pparγ in adipocytes and macrophages监管pparγ趋化因子和趋化因子受体表达的脂肪细胞和巨噬细胞.pdfVIP

Regulation of Chemokine and Chemokine Receptor Expression by PPARc in Adipocytes and Macrophages M. T. Audrey Nguyen.¤a, Ai Chen., Wendell J. Lu, WuQiang Fan, Ping-Ping Li, Da Young Oh, David Patsouris*¤b Department of Medicine (0673), University of California San Diego, La Jolla, California, United States of America Abstract Background: PPARc plays a key role in adipocyte biology, and Rosiglitazone (Rosi), a thiazolidinedione (TZD)/PPARc agonist, is a potent insulin-sensitizing agent. Recent evidences demonstrate that adipose tissue inflammation links obesity with insulin resistance and that the insulin-sensitizing effects of TZDs result, in part, from their anti-inflammatory properties. However the underlying mechanisms are unclear. Methodology and Principal Findings: In this study, we establish a link between free fatty acids (FFAs) and PPARc in the context of obesity-associated inflammation. We show that treatment of adipocytes with FFAs, in particular Arachidonic Acid (ARA), downregulates PPARc protein and mRNA levels. Furthermore, we demonstrate that the downregulation of PPARc by ARA requires the activation the of Endoplamsic Reticulum (ER) stress by the TLR4 pathway. Knockdown of adipocyte PPARc resulted in upregulation of MCP1 gene expression and secretion, leading to enhanced macrophage chemotaxis. Rosi inhibited these effects. In a high fat feeding mouse model, we show that Rosi treatment decreases recruitment of proinflammatory macrophages to epididymal fat. This correlates with decreased chemokine and decreased chemokine receptor expression in adipocytes and macrophages, respectively. Conclusions and Significance: In summary, we describe a novel link between FAs, the TLR4/ER stress pathway and PPARc, and adipocyte-driven recruitment of macrophages. We thus both d