title: High-Fat Diet Induces Unexpected Fatal Uterine Infections in Mice with aP2-Cre-mediated Deletion of Estrogen Receptor Alpha.
abstract: Estrogen receptor alpha (ERα) is a major regulator of metabolic processes in obesity. In this study we aimed to define the relevance of adipose tissue ERα during high-fat diet (HFD)-induced obesity using female aP2-Cre-/+/ERαfl/flmice (atERαKO). HFD did not affect body weight or glucose metabolism in atERαKO- compared to control mice. Surprisingly, HFD feeding markedly increased mortality in atERαKO mice associated with a destructive bacterial infection of the uterus driven by commensal microbes, an alteration likely explaining the absence of a metabolic phenotype in HFD-fed atERαKO mice. In order to identify a mechanism of the exaggerated uterine infection in HFD-fed atERαKO mice, a marked reduction of uterine M2-macrophages was detected, a cell type relevant for anti-microbial defence. In parallel, atERαKO mice exhibited elevated circulating estradiol (E2) acting on E2-responsive tissue/cells such as macrophages. Accompanying cell culture experiments showed that despite E2 co-administration stearic acid (C18:0), a fatty acid elevated in plasma from HFD-fed atERαKO mice, blocks M2-polarization, a process known to be enhanced by E2. In this study we demonstrate an unexpected phenotype in HFD-fed atERαKO involving severe uterine bacterial infections likely resulting from a previously unknown negative interference between dietary FAs and ERα-signaling during anti-microbial defence.
authors.affiliation: Charité-Universitaetsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Ban
authors.affiliation: Charité-Universitaetsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Maurischat
authors.affiliation: Charité-Universitaetsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Benz
authors.affiliation: Charité-Universitaetsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Brix
authors.affiliation: Charité-Universitaetsmedizin Berlin, Institute of Clinical Pharmacology and Toxicology, Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Sonnenburg
authors.affiliation: Clinic for Obstetrics, Gynaecology and Andrology of Large and Small Animals, Faculty of Veterinary Medicine, Justus-Liebig-Universität Gießen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Schuler
authors.affiliation: Department of Veterinary Pathology, College of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Klopfleisch
authors.affiliation: Lipidomix GmbH, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.affiliation: University of Houston, Center for Nuclear Receptors and Cell Signaling, Houston, TX, USA.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Charité-Universitaetsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Foryst-Ludwig
authors.affiliation: Charité-Universitaetsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001424:Bacterial Infections / Q000209:etiology*; D002478:Cells, Cultured; D059305:Diet, High-Fat; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D015398:Signal Transduction; D002575:Uterine Cervicitis / Q000378:metabolism / Q000382:microbiology*
chemical_list: D047628:Estrogen Receptor alpha