Estrogen receptor α activation modulates the gut microbiome and type 2 diabetes risk factors

Estradiol and exercise can decrease risk factors associated with type 2 diabetes (T2D) including total body weight gain and abdominal fat gain. Estradiol functions through estrogen receptor (ER) α and ERβ. Some studies suggest that activation of ERα may provide protection against T2D. Female Wistar rats were ovariectomized and fed a high‐fat diet for 10 weeks and divided into the following 5 experimental groups: (1) no treatment (control), (2) exercise, (3) estradiol, (4) propylpyrazoletriyl (a selective ERα agonist), and (5) diarylpropionitrile (a selective ERβ agonist). ERα activation decreased the abundance of Firmicutes, and ERα and ERβ activation increased the abundance of Bacteroidetes. ERα activation decreased food consumption, and ERα and ERβ activation increased voluntary activity. Exercise was the only treatment to decrease the blood glucose and serum insulin levels. ERα activation, but not ERβ, increased hepatic protein expression of ACC and FAS and decreased hepatic protein expression of LPL. ERα activation also decreased hepatic mRNA expression of PPARα and PPARγ. This study elucidates the functions of estradiol by assessing specific activation of ERα and ERβ. As obesity increases the abundance of Firmicutes and decreases the abundance of Bacteroidetes, our study shows that ERα activation can restore the gut microbiome to non‐obese abundances. This study further provides novel insights into ERα’s role in hepatic fat metabolism via regulation of ACC, FAS, LPL, PPARα, and PPARγ.