Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERα):: a potential role for estrogen receptor beta (ERβ)

Adipose tissue deposition is highly responsive to estrogen; ovariectomy increases adipose deposition, and estrogen replacement reverses this. Estrogen receptor a (ERalpha) plays a major role in adipose tissue. ERalpha knockout (alphaERKO) mice show an increase in adipose tissue of over a 100% compared to wild-type mice. However, alphaERKO mice undergo a 10-fold increase in 17beta-estradiol (E2), and persistent or even increased signaling through ER could be a factor in obesity of alphaERKO mice. To test the hypothesis that ERbeta plays a role in adipose tissue, adult female alphaERKO mice were ovariectomized or sham-ovariectomized and fed a phytoestrogen-free diet. Ovariectomized mice were treated with vehicle or E2, and bodyweights and food consumption were measured. Mice were killed after 28 days and inguinal and parametrial fat pads collected. Sham-ovariectomized alphaERKO mice had increased body weight, ovariectornized alphaERKO mice showed a 6% decrease, and E2 replacement restored body weight to sham levels. Fat pads of ovariectornized aERKO mice showed 45% and 16% decreases in weight and adipocyte circumference, respectively, compared to sham-ovariectomized or E2-replaced ovariectomized alphaERKO mice. Ovariectornized aERKO mice showed a trend towards decreased feed consumption that did not reach significance. Blood glucose levels were lower both before and after glucose injection in ovariectornized compared to sham alphaERKO mice, and E2 treatment reversed this. Insulin levels following glucose challenge were lower in ovariectomized compared to shamovariectomized alphaERKO mice, indicating that ovariectomy ameliorated the glucose intolerance and insulin resistance in alphaERKO mice. Immunohistochemical analysis revealed Strong staining for ERbeta in adipose tissue. These observations indicate that removing E2/ERbeta signaling in alphaERKO mice by ovariectomy decreases body and fat-pad weights and adipocyte size, while improving insulin and glucose metabolism. ERbeta mediated effects on adipose tissue are opposite those of ERalpha, although E2 effects on adipose tissue are predominately through ERalpha.