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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Animals
  • Bacterial Infections / etiology*
  • Cells, Cultured
  • Diet, High-Fat*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • Phagocytosis
  • Signal Transduction
  • Uterine Cervicitis / metabolism
  • Uterine Cervicitis / microbiology*


  • Estrogen Receptor alpha