Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA.
J Endocrinol. 2020 Apr;245(1):165-178. doi: 10.1530/JOE-19-0321.
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 (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) 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 αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.
卵巢激素的丧失会导致脂肪量增加和胰岛素抵抗（IR），从而增加心血管和代谢疾病的风险。本研究的目的是探讨卵巢切除术后全身和脂肪组织特定代谢不良影响的分子机制是否需要通过雌激素受体α（ERα）或雌激素受体β（ERβ）丧失信号。我们检查了卵巢切除（OVX）和卵巢完整野生型（WT）、ERα 缺失（αKO）和 ERβ 缺失（βKO）雌性小鼠（年龄~49 周；n=7-12/组）。所有小鼠均喂食不含植物雌激素的饮食（<15mg/kg），并保持卵巢完整（INT）或卵巢切除并随访 12 周。分析了身体成分、能量消耗、葡萄糖耐量以及脂肪组织基因和蛋白表达。与年龄匹配的 INT WT 对照和βKO 小鼠相比，INT αKO 小鼠的体脂率降低了约 25%，能量消耗降低（均 P<0.001）。OVX 后，与 WT 和βKO 不同，αKO 小鼠的肥胖程度没有增加，也没有出现进一步的 IR 增加，这表明 ERα 信号的丧失介导了 OVX 引起的代谢功能障碍。事实上，在 αKO 小鼠中进行 OVX（即 ERβ 在没有 ERα 的情况下发挥信号作用）导致脂肪减少、脂肪细胞大小减小和 IR（所有 P<0.05）。βKO 小鼠对 OVX 的反应是肥胖增加和 IR 发展。综上所述，这些发现挑战了在所有情况下 ERα 介导代谢保护优于 ERβ 的范式。这些发现使我们提出，在卵巢激素丧失后，ERβ 可能介导保护代谢益处。
