Adipose Tissue Estrogen Receptor-Alpha Overexpression Ameliorates High-Fat Diet-Induced Adipose Tissue Inflammation

We created an innovative mouse model that enables inducible overexpression of estrogen receptor-alpha (ERα), specifically in adipose tissue (Adipo-ERα↑).

We aimed to investigate how elevated Adipo-ERα↑ influences the development of high-fat diet (HFD)-induced obesity in both male and female mice.

Male and female Adipo-ERα↑ mice and littermate controls were fed a low-fat diet (LFD) or HFD for 13 weeks. Adipo-ERα↑ was induced at the initiation of dietary treatment. Body morphology and composition, hepatic lipid accumulation, glucose tolerance, fasting insulin concentrations, and adipose tissue mRNA profiling were assessed. Liquid chromatography-mass spectrometry was used to determine circulating and adipose tissue sex steroid content.

Adipo-ERα↑ significantly reduced adiposity and hepatic lipid accumulation in HFD-fed female mice but not in male mice. However, in both sexes, Adipo-ERα↑ greatly reduced adipose tissue inflammation characteristic of obesity. Despite these effects, Adipo-ERα↑ did not improve glucose tolerance or fasting insulin levels and did not affect circulating and adipose tissue sex steroid content.

Adipo-ERα↑ elicits distinct sex-specific effects with respect to body composition and hepatic lipid accumulation, which are likely driven by variations in circulating and tissue estrogen levels. Nonetheless, despite differences in estrogen levels, Adipo-ERα↑ profoundly reduced obesity-linked adipose tissue inflammation in both sexes, providing further evidence that therapeutically targeting ERα may be beneficial for treating obesity-associated inflammation.