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
