What have we learned about GPER function in physiology and disease from knockout mice
Open accessAbstract
Estrogens, predominantly 17β-estradiol, exert diverse effects throughout the body in both normal and pathophysiology, during development and in reproductive, metabolic, endocrine, cardiovascular, nervous, musculoskeletal and immune systems. Estrogen and its receptors also play important roles in carcinogenesis and therapy, particularly for breast cancer. In addition to the classical nuclear estrogen receptors (ERα and ERβ) that traditionally mediate predominantly genomic signaling, the G protein-coupled estrogen receptor GPER has become recognized as a critical mediator of rapid signaling in response to estrogen. Mouse models, and in particular knockout (KO) mice, represent an important approach to understand the functions of receptors in normal physiology and disease. Whereas ERα KO mice display multiple significant defects in reproduction and mammary gland development, ERβ KO phenotypes are more limited, and GPER KO exhibit no reproductive deficits. However, the study of GPER KO mice over the last six years has revealed that GPER deficiency results in multiple physiological alterations including obesity, cardiovascular dysfunction, insulin resistance and glucose intolerance. In addition, the lack of estrogen-mediated effects in numerous tissues of GPER KO mice, studied in vivo or ex vivo, including those of the cardiovascular, endocrine, nervous and immune systems, reveals GPER as a genuine mediator of estrogen action. Importantly, GPER KO mice have also demonstrated roles for GPER in breast carcinogenesis and metastasis. In combination with the supporting effects of GPER-selective ligands and GPER knockdown approaches, GPER KO mice demonstrate the therapeutic potential of targeting GPER activity in diseases as diverse as obesity, diabetes, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke and cancer.
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GPER1 knockout mice are more prone to obesity, insulin resistance, inflammation, and dyslipidemia than control mice.
“GPER1 KO mice are more prone to obesity, insulin resistance, inflammation, and dyslipidemia than control mice (147–149).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [149]
The Metabolic Functions section reports obesity, insulin resistance and dyslipidemia in GPER KO1 mice; the Immune functions section says aged KO1 mice exhibit a pro-inflammatory state (pages unavailable). But the review also reports no weight increase, or lower weight, in other knockout lines, and limits the insulin-resistance and dyslipidemia findings by sex, age or diet. The claim overgeneralizes these findings to GPER1 knockout mice as a group. (LLM, conf=0.87)
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The G protein‐coupled receptor (GPER/GPR30) activates endothelial nitric oxide synthase (1075.5)
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Molecular mechanism of estrogen–estrogen receptor signaling
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Does GPER Really Function as a G Protein-Coupled Estrogen Receptor in vivo?
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Self-citationEstrogens regulate life and death in mitochondria
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Role of GPER in estrogen-dependent nitric oxide formation and vasodilation
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Self-citationTorre, S. D. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.572490 · Cited by 118 · see citing works
GPER–novel membrane oestrogen receptor
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Self-citation30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor
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Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes
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Self-citationG-Protein Coupled Estrogen Receptor in Breast Cancer
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G-Protein-Coupled Estrogen Receptor (GPER) and Sex-Specific Metabolic Homeostasis
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Self-citationUnraveling the Dynamics of Estrogen and Progesterone Signaling in the Endometrium: An Overview
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Emerging roles for the novel estrogen-sensing receptor GPER1 in the CNS
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Obligatory role for GPER in cardiovascular aging and disease
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G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis
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Self-citationEndocrine Disrupting Chemicals, Hormone Receptors, and Acne Vulgaris: A Connecting Hypothesis
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Sex Hormones Regulate Cytoskeletal Proteins Involved in Brain Plasticity
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Innate Sex Bias of Staphylococcus aureus Skin Infection Is Driven by α-Hemolysin
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Self-citationThe Interface of Nuclear and Membrane Steroid Signaling
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G Protein-Coupled Estrogen Receptor 1 Regulates Human Neutrophil Functions
Rodenas, M. C., Tamassia, N., Cabas, I., Calzetti, F., Meseguer, J., Cassatella, M. A., Ayala, A. G., & Mulero, V. (2017) · Biomedicine Hub · doi:10.1159/000454981 · Cited by 52 · see citing works
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Estrogens and development of the rete testis, efferent ductules, epididymis and vas deferens
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Estrogens: Two nuclear receptors, multiple possibilities
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Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers
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Estrogen Activation by Steroid Sulfatase Increases Colorectal Cancer Proliferation via GPER
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Therapeutic Perspectives on the Modulation of G-Protein Coupled Estrogen Receptor, GPER, Function
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Role of G Protein-Coupled Estrogen Receptor in Cancer Progression
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Skeletal muscle wasting: the estrogen side of sexual dimorphism
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GPER as a Receptor for Endocrine-Disrupting Chemicals (EDCs)
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Importance of Estrogenic Signaling and Its Mediated Receptors in Prostate Cancer
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GPER/GPR30 Knockout Mice: Effects of GPER on Metabolism
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Macromolecular Modelling and Docking Simulations for the Discovery of Selective GPER Ligands
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Targeting the G protein-coupled estrogen receptor (GPER) in obesity and diabetes
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Self-citationStructure–Activity Relationship of para-Carborane Selective Estrogen Receptor β Agonists
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Role of estrogens in fish immunity with special emphasis on GPER1
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GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer
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The G Protein-Coupled Estrogen Receptor (GPER): A Critical Therapeutic Target for Cancer
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Varying Susceptibility of the Female Mammary Gland to In Utero Windows of BPA Exposure
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GPER modulators: Opportunity Nox on the heels of a class Akt
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Non-Coding RNAs Modulating Estrogen Signaling and Response to Endocrine Therapy in Breast Cancer
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Role of GPER in the anterior pituitary gland focusing on lactotroph function
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Sexual Dimorphism in Cardiometabolic Diseases: The Role of AMPK
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Estrogen dysregulation, intraocular pressure, and glaucoma risk
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PELP 1: a key mediator of oestrogen signalling and actions in the brain
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A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling
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Estrogen Receptor Knockout Mice and Their Effects on Fertility
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Ovaries of estrogen receptor 1-deficient mice show iron overload and signs of aging
Schröder, S. K., Krizanac, M., Kim, P., Kessel, J. C., & Weiskirchen, R. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1325386 · Cited by 14 · see citing works
G protein-coupled estrogen receptor biased signaling in health and disease
Bushi, A., Ma, Y., Adu‐Amankwaah, J., Wang, R., Cui, F., Xiao, R., Zhao, J., Yuan, J., & Tan, R. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108822 · Cited by 14 · see citing works
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GPER was associated with hypertension in post-menopausal women
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Female Sex Hormone Receptor Profiling in Uterine Adenosarcomas
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- Authors
- Prossnitz, E. R., & Hathaway, H. J.
- Affiliations
- University of New Mexico (US)
- Corresponding author
- Prossnitz, Eric R.
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 153
- Pages
- 114-126
- ISSN
- 0960-0760 (ISSN-L)
- PMC
- PMC4568147
- OpenAlex
- W923732998
- Cited by
- 157
- References
- 202
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 11 · 2023: 14 · 2022: 11 · 2021: 18 · 2020: 18 · 2019: 15 · 2018: 12 · 2017: 25 · 2016: 9 · 2015: 4
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001449)
- National Cancer Institute (R01CA116662, R01CA127731, R01CA118743, R01CA163890, P30CA118100)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- G protein-coupled estrogen receptor, estrogen signaling, rapid estrogen signaling, obesity, insulin resistance, impaired glucose tolerance, cardiovascular dysfunction, breast cancer, breast metastasis, estrogen receptor alpha, estrogen receptor beta, multiple sclerosis, hypertension, atherosclerosis, myocardial infarction, stroke, diabetes mellitus
- MeSH terms
- Animals, Cardiovascular Diseases, Diabetes Mellitus, Disease Models, Animal, Humans, Immunity, Neoplasms, Obesity, Receptors, Estrogen, Mice, Knockout, Receptors, G-Protein-Coupled, Mice
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