Document Detail


Regulation of chemokine and chemokine receptor expression by PPARγ in adipocytes and macrophages.
MedLine Citation:
PMID:  22529965     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
M T Audrey Nguyen; Ai Chen; Wendell J Lu; Wuqiang Fan; Ping-Ping Li; Da Young Oh; David Patsouris
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-17
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-04-24     Completed Date:  2012-11-19     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e34976     Citation Subset:  IM    
Affiliation:
Department of Medicine (0673), University of California San Diego, La Jolla, California, United States of America.
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MeSH Terms
Descriptor/Qualifier:
Adipocytes / drug effects,  metabolism*
Adipose Tissue / drug effects,  metabolism
Animals
Arachidonic Acid / pharmacology
Chemokines / metabolism*
Chemotactic Factors / secretion
Down-Regulation
Endoplasmic Reticulum Stress / genetics
Fatty Acids, Nonesterified / pharmacology
Gene Expression / drug effects
Hypoglycemic Agents / pharmacology
Macrophages / metabolism*
Male
Mice
Mice, Inbred C57BL
PPAR gamma / genetics,  metabolism*
Receptors, Chemokine / metabolism*
Signal Transduction
Thiazolidinediones / pharmacology
Toll-Like Receptor 4 / metabolism
Grant Support
ID/Acronym/Agency:
DK033651/DK/NIDDK NIH HHS; DK063491/DK/NIDDK NIH HHS; DK074868/DK/NIDDK NIH HHS; T32 DK 007494/DK/NIDDK NIH HHS; U54 HD 012303-25/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Chemokines; 0/Chemotactic Factors; 0/Fatty Acids, Nonesterified; 0/Hypoglycemic Agents; 0/PPAR gamma; 0/Receptors, Chemokine; 0/Thiazolidinediones; 0/Toll-Like Receptor 4; 122320-73-4/rosiglitazone; 506-32-1/Arachidonic Acid
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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