title: Erythropoietin signaling: a novel regulator of white adipose tissue inflammation during diet-induced obesity.
abstract: 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.
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Mawadda
authors.initials: M
authors.lastname: Alnaeeli
authors.affiliation: Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Raaka
authors.affiliation: Mouse Metabolism Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: Mouse Metabolism Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Teng
authors.affiliation: Mouse Metabolism Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Chanturiya
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD connien@helix.nih.gov.
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D052436:Adipose Tissue, White / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004921:Erythropoietin / Q000502:physiology*; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D015434:Panniculitis / Q000235:genetics* / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017467:Receptors, Erythropoietin; D004921:Erythropoietin