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The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity

With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E(2) suppresses macrophage activation via EP4; however, the role of...

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Autores principales: Yasui, Mika, Tamura, Yukinori, Minami, Manabu, Higuchi, Sei, Fujikawa, Risako, Ikedo, Taichi, Nagata, Manabu, Arai, Hidenori, Murayama, Toshinori, Yokode, Masayuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550358/
https://www.ncbi.nlm.nih.gov/pubmed/26308623
http://dx.doi.org/10.1371/journal.pone.0136304
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author Yasui, Mika
Tamura, Yukinori
Minami, Manabu
Higuchi, Sei
Fujikawa, Risako
Ikedo, Taichi
Nagata, Manabu
Arai, Hidenori
Murayama, Toshinori
Yokode, Masayuki
author_facet Yasui, Mika
Tamura, Yukinori
Minami, Manabu
Higuchi, Sei
Fujikawa, Risako
Ikedo, Taichi
Nagata, Manabu
Arai, Hidenori
Murayama, Toshinori
Yokode, Masayuki
author_sort Yasui, Mika
collection PubMed
description With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E(2) suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist–treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle–treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator–activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator–activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.
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spelling pubmed-45503582015-09-01 The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity Yasui, Mika Tamura, Yukinori Minami, Manabu Higuchi, Sei Fujikawa, Risako Ikedo, Taichi Nagata, Manabu Arai, Hidenori Murayama, Toshinori Yokode, Masayuki PLoS One Research Article With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E(2) suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist–treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle–treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator–activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator–activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus. Public Library of Science 2015-08-26 /pmc/articles/PMC4550358/ /pubmed/26308623 http://dx.doi.org/10.1371/journal.pone.0136304 Text en © 2015 Yasui 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
Yasui, Mika
Tamura, Yukinori
Minami, Manabu
Higuchi, Sei
Fujikawa, Risako
Ikedo, Taichi
Nagata, Manabu
Arai, Hidenori
Murayama, Toshinori
Yokode, Masayuki
The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity
title The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity
title_full The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity
title_fullStr The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity
title_full_unstemmed The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity
title_short The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity
title_sort prostaglandin e2 receptor ep4 regulates obesity-related inflammation and insulin sensitivity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550358/
https://www.ncbi.nlm.nih.gov/pubmed/26308623
http://dx.doi.org/10.1371/journal.pone.0136304
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