Erythropoietin Signaling: A Novel Regulator of White Adipose Tissue Inflammation During Diet-Induced Obesity
- Mawadda Alnaeeli1,
- Bruce M. Raaka2,
- Oksana Gavrilova3,
- Ruifeng Teng3,
- Tatyana Chanturiya3 and
- Constance Tom Noguchi1⇑
- 1Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
- 2Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
- 3Mouse Metabolism Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
- Corresponding author: Constance Tom Noguchi, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0883/-/DC1.
M.A. is currently affiliated with the Department of Biological Sciences, Ohio University, Zanesville, OH, and the Diabetes Institute at Ohio University, Athens, OH.
See accompanying article, p. 2229.
- Received June 5, 2013.
- Accepted March 5, 2014.
- © 2014 by the American Diabetes Association.
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