Effect of Ovariectomy on Adipose Tissue of Mice in the Absence of Estrogen Receptor Alpha (ERα): a Potential Role for Estrogen Receptor Beta (ERβ)

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Abstract
Adipose tissue deposition is highly responsive to estrogen; ovariectomy increases adipose deposition, and estrogen replacement reverses this. Estrogen receptor α (ERα) plays a major role in adipose tissue. ERα knockout (αERKO) mice show an increase in adipose tissue of over a 100 % compared to wild-type mice. However, αERKO mice undergo a 10-fold increase in 17β-estradiol (E2), and persistent or even increased signaling through ERβ could be a factor in obesity of αERKO mice. To test the hypothesis that ERβ plays a role in adipose tissue, adult female αERKO 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 αERKO mice had increased body weight, ovariectomized αERKO mice showed a 6 % decrease, and E2 replacement restored body weight to sham levels. Fat pads of ovariectomized αERKO mice showed 45 % and 16 % decreases in weight and adipocyte circumference, respectively, compared to sham-ovariectomized or E2-replaced ovariectomized αERKO mice. Ovariectomized αERKO 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 ovariectomized compared to sham αERKO mice, and E2 treatment reversed this. Insulin levels following glucose challenge were lower in ovariectomized compared to sham-ovariectomized αERKO mice, indicating that ovariectomy ameliorated the glucose intolerance and insulin resistance in αERKO mice. Immunohistochemical analysis revealed strong staining for ERβ in adipose tissue. These observations indicate that removing E2/ERβ signaling in αERKO mice by ovariectomy decreases body and fat-pad weights and adipocyte size, while improving insulin and glucose metabolism. ERβ mediated effects on adipose tissue are opposite those of ERα, although E2 effects on adipose tissue are predominately through ERα.

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