| Regulation of chemokine and chemokine receptor expression by PPARγ in adipocytes and macrophages. | |
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MedLine Citation:
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PMID: 22529965 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-04-17 |
Journal Detail:
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Title: PloS one Volume: 7 ISSN: 1932-6203 ISO Abbreviation: PLoS ONE Publication Date: 2012 |
Date Detail:
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Created Date: 2012-04-24 Completed Date: 2012-11-19 Revised Date: 2013-05-20 |
Medline Journal Info:
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Nlm Unique ID: 101285081 Medline TA: PLoS One Country: United States |
Other Details:
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Languages: eng Pagination: e34976 Citation Subset: IM |
Affiliation:
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Department of Medicine (0673), University of California San Diego, La Jolla, California, United States of America. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipocytes
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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:
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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:
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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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