Effects Of Er Ss And Er Alpha 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 requ ires loss of signaling through estrogen receptor alpha (ER alpha) or estrogen receptor ss (ER ss). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ER alpha-null (alpha KO), and ER ss-null (ss KO) female mice (age similar to 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 alpha KO were similar to 25% fatter with reduced energy expenditure compared to age-matched INT WT controls and ss KO mice (all P < 0.001). Following OVX, alpha KO mice did not increase adiposity or experience a further increase in IR, unlike WT and ss KO, suggesting that loss of signaling through ER alpha mediates OVX-induced metabolic dysfunction. In fact, OVX in alpha KO mice (i.e., signaling through ER ss in the absence of ER alpha) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). ss KO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradi gm that ER alpha mediates metabolic protection over ER ss in all settings. These findings lead us to suggest that, following ovarian hormone loss, ER ss may mediate protective metabolic benefits.