title: Regulation of chemokine and chemokine receptor expression by PPARγ in adipocytes and macrophages.
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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Department of Medicine (0673), University of California San Diego, La Jolla, California, United States of America.
authors.forename: M T Audrey
authors.initials: MT
authors.lastname: Nguyen
authors.forename: Ai
authors.initials: A
authors.lastname: Chen
authors.forename: Wendell J
authors.initials: WJ
authors.lastname: Lu
authors.forename: Wuqiang
authors.initials: W
authors.lastname: Fan
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Li
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
authors.forename: David
authors.initials: D
authors.lastname: Patsouris
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D018925:Chemokines; D002630:Chemotactic Factors; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D019707:Receptors, Chemokine; D045162:Thiazolidinediones; D051197:Toll-Like Receptor 4; D000077154:Rosiglitazone; D016718:Arachidonic Acid