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Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages
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 effe...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328487/ https://www.ncbi.nlm.nih.gov/pubmed/22529965 http://dx.doi.org/10.1371/journal.pone.0034976 |
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author | Nguyen, M. T. Audrey Chen, Ai Lu, Wendell J. Fan, WuQiang Li, Ping-Ping Oh, Da Young Patsouris, David |
author_facet | Nguyen, M. T. Audrey Chen, Ai Lu, Wendell J. Fan, WuQiang Li, Ping-Ping Oh, Da Young Patsouris, David |
author_sort | Nguyen, M. T. Audrey |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3328487 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33284872012-04-23 Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages Nguyen, M. T. Audrey Chen, Ai Lu, Wendell J. Fan, WuQiang Li, Ping-Ping Oh, Da Young Patsouris, David PLoS One Research Article 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. Public Library of Science 2012-04-17 /pmc/articles/PMC3328487/ /pubmed/22529965 http://dx.doi.org/10.1371/journal.pone.0034976 Text en Nguyen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Nguyen, M. T. Audrey Chen, Ai Lu, Wendell J. Fan, WuQiang Li, Ping-Ping Oh, Da Young Patsouris, David Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages |
title | Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages |
title_full | Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages |
title_fullStr | Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages |
title_full_unstemmed | Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages |
title_short | Regulation of Chemokine and Chemokine Receptor Expression by PPARγ in Adipocytes and Macrophages |
title_sort | regulation of chemokine and chemokine receptor expression by pparγ in adipocytes and macrophages |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328487/ https://www.ncbi.nlm.nih.gov/pubmed/22529965 http://dx.doi.org/10.1371/journal.pone.0034976 |
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