Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity

Obesity-induced white adipose tissue (WAT) inflammation and insulin resistance are associated with macrophage (Mф) infiltration and phenotypic shift from “anti-inflammatory” M2-like to predominantly “proinflammatory” M1-like cells. Erythropoietin (EPO), a glycoprotein hormone indispensable for eryth...

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Autores principales: Alnaeeli, Mawadda, Raaka, Bruce M., Gavrilova, Oksana, Teng, Ruifeng, Chanturiya, Tatyana, Noguchi, Constance Tom
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066343/
https://www.ncbi.nlm.nih.gov/pubmed/24647735
http://dx.doi.org/10.2337/db13-0883
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author Alnaeeli, Mawadda
Raaka, Bruce M.
Gavrilova, Oksana
Teng, Ruifeng
Chanturiya, Tatyana
Noguchi, Constance Tom
author_facet Alnaeeli, Mawadda
Raaka, Bruce M.
Gavrilova, Oksana
Teng, Ruifeng
Chanturiya, Tatyana
Noguchi, Constance Tom
author_sort Alnaeeli, Mawadda
collection PubMed
description Obesity-induced white adipose tissue (WAT) inflammation and insulin resistance are associated with macrophage (Mф) infiltration and phenotypic shift from “anti-inflammatory” M2-like to predominantly “proinflammatory” M1-like cells. Erythropoietin (EPO), a glycoprotein hormone indispensable for erythropoiesis, has biological activities that extend to nonerythroid tissues, including antiapoptotic and anti-inflammatory effects. Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance. We investigated EPO receptor (EPO-R) expression in WAT and characterized the role of its signaling during obesity-induced inflammation. Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like Mф and increased M2-like Mф in WAT, while decreasing inflammatory monocytes. These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in Mф via Stat3 activation, where EPO effects on M2 but not M1 Mф required interleukin-4 receptor/Stat6. Using obese ∆EpoR mice with EPO-R restricted to erythroid cells, we demonstrated an anti-inflammatory role for endogenous EPO. Collectively, our findings identify EPO-R signaling as a novel regulator of WAT inflammation, extending its nonerythroid activity to encompass effects on both Mф infiltration and subset composition in WAT.
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spelling pubmed-40663432015-07-01 Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity Alnaeeli, Mawadda Raaka, Bruce M. Gavrilova, Oksana Teng, Ruifeng Chanturiya, Tatyana Noguchi, Constance Tom Diabetes Pathophysiology Obesity-induced white adipose tissue (WAT) inflammation and insulin resistance are associated with macrophage (Mф) infiltration and phenotypic shift from “anti-inflammatory” M2-like to predominantly “proinflammatory” M1-like cells. Erythropoietin (EPO), a glycoprotein hormone indispensable for erythropoiesis, has biological activities that extend to nonerythroid tissues, including antiapoptotic and anti-inflammatory effects. Using comprehensive in vivo and in vitro analyses in mice, EPO treatment inhibited WAT inflammation, normalized insulin sensitivity, and reduced glucose intolerance. We investigated EPO receptor (EPO-R) expression in WAT and characterized the role of its signaling during obesity-induced inflammation. Remarkably, and prior to any detectable changes in body weight or composition, EPO treatment reduced M1-like Mф and increased M2-like Mф in WAT, while decreasing inflammatory monocytes. These anti-inflammatory effects were found to be driven, at least in part, by direct EPO-R response in Mф via Stat3 activation, where EPO effects on M2 but not M1 Mф required interleukin-4 receptor/Stat6. Using obese ∆EpoR mice with EPO-R restricted to erythroid cells, we demonstrated an anti-inflammatory role for endogenous EPO. Collectively, our findings identify EPO-R signaling as a novel regulator of WAT inflammation, extending its nonerythroid activity to encompass effects on both Mф infiltration and subset composition in WAT. American Diabetes Association 2014-07 2014-06-14 /pmc/articles/PMC4066343/ /pubmed/24647735 http://dx.doi.org/10.2337/db13-0883 Text en © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Pathophysiology
Alnaeeli, Mawadda
Raaka, Bruce M.
Gavrilova, Oksana
Teng, Ruifeng
Chanturiya, Tatyana
Noguchi, Constance Tom
Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity
title Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity
title_full Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity
title_fullStr Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity
title_full_unstemmed Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity
title_short Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity
title_sort erythropoietin signaling: a novel regulator of white adipose tissue inflammation during diet-induced obesity
topic Pathophysiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066343/
https://www.ncbi.nlm.nih.gov/pubmed/24647735
http://dx.doi.org/10.2337/db13-0883
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