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Updated: Dec 28, 2025
An In Vivo Estrogen Deficiency Mouse Model for Screening Exogenous Estrogen Treatments of Cardiovascular Dysfunction After Menopause
Published on: August 13, 2019
Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance
Terese M Zidon1, Jaume Padilla1,2, Kevin L Fritsche1
1Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA.
Abstract:
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.
Insights
Ovariectomy-induced metabolic dysfunction, including increased adiposity and insulin resistance, is mediated by estrogen receptor alpha (ERα). Estrogen receptor beta (ERβ) may offer protective metabolic benefits after ovarian hormone loss.
Area of Science:
- Endocrinology
- Metabolic disease research
- Reproductive biology
Background:
- Loss of ovarian hormones is linked to increased adiposity and insulin resistance (IR).
- This metabolic dysfunction elevates the risk for cardiovascular and metabolic diseases.
- The specific roles of estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) in these effects are not fully understood.
Purpose of the Study:
- To investigate whether ovariectomy-induced metabolic changes depend on signaling through ERα or ERβ.
- To determine the distinct contributions of ERα and ERβ to systemic and adipose tissue metabolism following ovarian hormone loss.
Main Methods:
- Ovariectomized (OVX) and ovary-intact wild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice were studied.
- Mice were fed a phytoestrogen-free diet for 12 weeks post-ovariectomy.
- Analyses included body composition, energy expenditure, glucose tolerance, and adipose tissue gene/protein expression.
Main Results:
- Intact αKO mice exhibited higher adiposity and lower energy expenditure than WT and βKO controls.
- OVX did not worsen adiposity or IR in αKO mice, indicating ERα signaling mediates OVX-induced metabolic dysfunction.
- OVX in αKO mice (ERβ signaling only) reduced adiposity, adipocyte size, and IR; βKO mice showed adverse effects post-OVX.
Conclusions:
- Loss of ERα signaling, not ERβ, mediates ovariectomy-induced metabolic dysfunction.
- ERβ signaling may confer protective metabolic benefits following ovarian hormone loss, challenging existing paradigms.
- These findings suggest a context-dependent role for ERα and ERβ in metabolic regulation.
