Regulation of chemokine and chemokine receptor expression by PPARγ in adipocytes and macrophages

M. T.Audrey Nguyen, Ai Chen, Wendell J. Lu, Wu Qiang Fan, Ping Ping Li, Dayoung Oh, David Patsouris

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Background: PPARγ plays a key role in adipocyte biology, and Rosiglitazone (Rosi), a thiazolidinedione (TZD)/PPARγ 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 PPARγ in the context of obesity-associated inflammation. We show that treatment of adipocytes with FFAs, in particular Arachidonic Acid (ARA), downregulates PPARγ protein and mRNA levels. Furthermore, we demonstrate that the downregulation of PPARγ by ARA requires the activation the of Endoplamsic Reticulum (ER) stress by the TLR4 pathway. Knockdown of adipocyte PPARγ 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 PPARγ, and adipocyte-driven recruitment of macrophages. We thus both describe an additional potential mechanism for the anti-inflammatory and insulin-sensitizing actions of TZDs and an additional detrimental property associated with the activation of the TLR4 pathway by FA.

Original languageEnglish (US)
Article numbere34976
JournalPloS one
Volume7
Issue number4
DOIs
StatePublished - Apr 17 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Nguyen, M. T. A., Chen, A., Lu, W. J., Fan, W. Q., Li, P. P., Oh, D., & Patsouris, D. (2012). Regulation of chemokine and chemokine receptor expression by PPARγ in adipocytes and macrophages. PloS one, 7(4), [e34976]. https://doi.org/10.1371/journal.pone.0034976