Insights of the role of estrogen in obesity from two models of ERα deletion

Sex hormones play a pivotal role in physiology and disease. Estrogen, the female sex hormone, has been long implicated in having protective roles against obesity. However, the direct impact of estrogens in white adipose tissue (WAT) function and growth are not understood. Here, we show that deletion of estrogen receptor alpha (ERα) from adipocytes using Adiponectin-cre does not affect adipose mass in male or female mice under normal or high-fat diet (HFD) conditions. However, loss of ERα in adipocyte precursor cells (APs) via PdgfRα-cre leads to exacerbated obesity upon HFD feeding in both male and female mice, with subcutaneous adipose (SWAT)-specific expansion in male mice. Further characterization of these mice revealed infertility and increased plasma levels of sex hormones, including estradiol in female mice and androgens in male mice. These findings compromise the study of estrogen signaling within the adipocyte lineage using the PdgfRα-cre strain. However, AP transplant studies demonstrate that the increased AP hyperplasia in male SWAT upon PdgfRα-cre -mediated ablation of ERα is not driven by AP-intrinsic mechanisms, but are rather mediated by off-target effects. These data highlight the inherent difficulties in studying models that disrupt the intricate balance of sex hormones. Thus, better approaches are needed to study the cellular and molecular mechanisms of sex hormones in obesity and disease.