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Sci Rep. 2017 Feb 24;7:43269. doi: 10.1038/srep43269.

High-Fat Diet Induces Unexpected Fatal Uterine Infections in Mice with aP2-Cre-mediated Deletion of Estrogen Receptor Alpha.

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Charité-Universitaetsmedizin Berlin, Institute of Pharmacology, Center for Cardiovascular Research, Berlin, Germany.
Charité-Universitaetsmedizin Berlin, Institute of Clinical Pharmacology and Toxicology, Berlin, Germany.
Clinic for Obstetrics, Gynaecology and Andrology of Large and Small Animals, Faculty of Veterinary Medicine, Justus-Liebig-Universität Gießen, Germany.
Department of Veterinary Pathology, College of Veterinary Medicine, Freie Universität Berlin, Berlin, Germany.
Lipidomix GmbH, Berlin, Germany.
University of Houston, Center for Nuclear Receptors and Cell Signaling, Houston, TX, USA.
DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany.


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/fl mice (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.

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