What have we learned about GPER function in physiology and disease from knockout mice?

Area of Science:

• Endocrinology
• Molecular Biology
• Physiology

Background:

• Estrogens exert broad physiological effects via nuclear receptors (ERα, ERβ) and the G protein-coupled estrogen receptor (GPER).
• Estrogen receptors are implicated in development, reproduction, metabolism, and carcinogenesis, including breast cancer.
• Mouse models, particularly knockout (KO) mice, are vital for dissecting receptor functions in health and disease.

Purpose of the Study:

• To investigate the physiological roles of the G protein-coupled estrogen receptor (GPER) using GPER knockout (KO) mouse models.
• To elucidate GPER's contribution to estrogen signaling beyond classical nuclear receptors.
• To explore the therapeutic potential of targeting GPER in various diseases.

Main Methods:

• Utilized GPER knockout (KO) mouse models to study GPER function in vivo and ex vivo.
• Analyzed physiological alterations in GPER KO mice, including metabolic, cardiovascular, and reproductive parameters.
• Investigated the role of GPER in breast cancer development and metastasis, alongside studies with GPER-selective ligands and knockdown approaches.

Main Results:

• GPER KO mice exhibited significant physiological alterations, including obesity, cardiovascular dysfunction, insulin resistance, and glucose intolerance.
• GPER deficiency led to a lack of estrogen-mediated effects in cardiovascular, endocrine, nervous, and immune systems, confirming GPER as a key estrogen mediator.
• GPER KO mice demonstrated GPER's involvement in breast carcinogenesis and metastasis.

Conclusions:

• GPER is a critical mediator of rapid estrogen signaling with significant roles in metabolic and cardiovascular health.
• GPER plays a crucial role in mediating estrogen's effects across multiple organ systems.
• Targeting GPER presents therapeutic potential for diverse conditions, including obesity, diabetes, cardiovascular diseases, and cancer.