Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERalpha) or estrogen receptor beta (ERbeta). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERalpha-null (alphaKO), and ERbeta-null (betaKO) female mice (age ~49 weeks; n = 7-12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT alphaKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and betaKO mice (all P < 0.001). Following OVX, alphaKO mice did not increase adiposity or experience a further increase in IR, unlike WT and betaKO, suggesting that loss of signaling through ERalpha mediates OVX-induced metabolic dysfunction. In fact, OVX in alphaKO mice (i.e., signaling through ERbeta in the absence of ERalpha) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). betaKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERalpha mediates metabolic protection over ERbeta in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERbeta may mediate protective metabolic benefits.