Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver
Open accessAbstract
Aims/hypothesis We used oestrogen receptor-alpha (ERalpha) knockout (ERKO) and receptor-beta (ERbeta) knockout (BERKO) mice to investigate the mechanism(s) behind the effects of oestrogens on glucose homeostasis.Methods Endogenous glucose production (EGP) was measured in ERKO mice using a euglycaemic-hyperinsulinaemic clamp. Insulin secretion was determined from isolated islets. In isolated muscles, glucose uptake was assayed by using radiolabelled isotopes. Genome-wide expression profiles were analysed by high-density oligonucleotide microarray assay, and the expression of the genes encoding steroyl-CoA desaturase and the Leptin receptor (Scd1 and Lepr, respectively) was confirmed by RT-PCR.Results ERKO mice had higher fasting blood glucose, plasma insulin levels and IGT. The plasma leptin level was increased, while the adiponectin concentration was decreased in ERKO mice. Levels of both glucose- and arginine-induced insulin secretion from isolated islets were similar in ERKO and wild-type mice. The euglycaemic-hyperinsulinaemic clamp revealed that suppression of EGP by increased insulin levels was blunted in ERKO mice, which suggests a pronounced hepatic insulin resistance. Microarray analysis revealed that in ERKO mice, the genes involved in hepatic lipid biosynthesis were upregulated, while genes involved in lipid transport were downregulated. Notably, hepatic Lepr expression was decreased in ERKO mice. In vitro studies showed a modest decrease in insulin-mediated glucose uptake in soleus and extensor digitorum longus (EDL) muscles of ERKO mice. BERKO mice demonstrated normal glucose tolerance and insulin release.Conclusions/interpretation We conclude that oestrogens, acting via ERalpha, regulate glucose homeostasis mainly by modulating hepatic insulin sensitivity, which can be due to the upregulation of lipogenic genes via the suppression of Lepr expression.
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ERα knockout mice in both males and females have worse metabolic profiles including developing obesity and worsened glucose homeostasis.
“ERα knockout (KO) mice in both males and females have worse metabolic profiles including developing obesity and worsened glucose homeostasis (90, 143–145).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [143]
The Characteristics of animals section reports higher fasting glucose and impaired glucose tolerance in both female and male ERα-knockout mice. It also reports 20% higher body weight in females, but similar body weights in knockout and wild-type males, so this paper does not support obesity in both sexes. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn mice, estrogens act via ERα and GPER1 to regulate insulin sensitivity.
“In mice, estrogens act via ERα and GPER1 to regulate insulin sensitivity (143).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [143]
The Discussion reports that loss of ERα caused insulin resistance in male and female mice, supporting the ERα part of the claim. The paper does not identify GPER1 as a mediator; its Introduction discusses ERα and ERβ instead. No page numbers are available in our copy. (LLM, conf=0.90)
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References 49 · Cited by 384
- Authors
- Bryzgalova, G., Gao, H., Ahren, B., Zierath, J. R., Galuska, D., Steiler, T. L., Dahlman-Wright, K., Nilsson, S., Gustafsson, J.-Å., Efendic, S., & Khan, A.
- Affiliations
- Karolinska University Hospital (SE)
- Karolinska Institutet (SE)
- Karo Pharma (Sweden) (SE)
- Corresponding author
- Bryzgalova, G.
- Venue
- Diabetologia
- Published
- 2006-02-04
- Volume
- 49
- Issue
- 3
- Pages
- 588-597
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2012740498
- Cited by
- 384
- References
- 49
- Citations by year
- 2026: 7 · 2025: 16 · 2024: 14 · 2023: 27 · 2022: 23 · 2021: 17 · 2020: 20 · 2019: 19 · 2018: 33 · 2017: 21 · 2016: 20 · 2015: 25 · 2014: 19 · 2013: 22 · 2012: 15
- FWCI
- 8.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- European Commission
- Vetenskapsrådet (00034)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- estrogen receptor alpha, estrogen receptor beta, glucose homeostasis, hepatic insulin resistance, insulin sensitivity, endogenous glucose production, leptin receptor, adiponectin, insulin secretion, insulin-stimulated glucose uptake, glucose tolerance, insulin resistance
- MeSH terms
- Insulin Secretion, Animals, Female, Glucose, Homeostasis, Insulin, Islets of Langerhans, Liver, Mice, Inbred C57BL, Sensitivity and Specificity, Mice, Knockout, Muscle, Skeletal, Leptin, Gene Expression Profiling, Estrogen Receptor alpha, Mice, Adiponectin, Resistin, In Vitro Techniques
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