The impact of ERα action on muscle metabolism and insulin sensitivity – Strong enough for a man, made for a woman
Open accessAbstract
BACKGROUND: The incidence of chronic disease is elevated in women after menopause. Natural variation in muscle expression of the estrogen receptor (ER)α is inversely associated with plasma insulin and adiposity. Moreover, reduced muscle ERα expression levels are observed in women and animals presenting clinical features of the metabolic syndrome (MetSyn). Considering that metabolic dysfunction impacts nearly a quarter of the U.S. adult population and elevates chronic disease risk including type 2 diabetes, heart disease, and certain cancers, treatment strategies to combat metabolic dysfunction and associated pathologies are desperately needed. SCOPE OF THE REVIEW: This review will provide evidence supporting a critical and protective role for skeletal muscle ERα in the regulation of metabolic homeostasis and insulin sensitivity, and propose novel ERα targets involved in the maintenance of metabolic health. MAJOR CONCLUSIONS: Studies identifying ERα-regulated pathways essential for disease prevention will lay the important foundation for the rational design of novel therapeutics to improve the metabolic health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.
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Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity and prevention of lipid accumulation and inflammation.
“Estrogen actions in skeletal muscle, liver, adipose tissue, and immune cells are involved in insulin sensitivity as well as prevention of lipid accumulation and inflammation [20,21,67,68].”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [20]
The sections on insulin action and skeletal-muscle fatty-acid metabolism link ERα to insulin sensitivity, fatty-acid oxidation, and inflammation in muscle. The paper also says ERα is expressed in liver, adipose tissue, and immune cells, but the retrieved passages do not establish that its actions in each of those tissues prevent lipid accumulation and inflammation. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRobust evidence demonstrates that estrogen and progesterone have important roles in regulating substrate metabolism.
“Robust evidence exists that demonstrates the important roles estrogen and progesterone have in regulating substrate metabolism [20,24,66,70,80,82,84,154–159].”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [20]
The section on ERα and skeletal muscle fatty acid metabolism reports that estrogen affects lipid oxidation, supporting its role in substrate metabolism (page unavailable). The section on insulin action and glucose disposal says progesterone can antagonize GLUT4 expression, but the paper calls for further study of progesterone’s metabolic effects; it does not establish equally robust evidence for progesterone’s broader role. (LLM, conf=0.82)
Experimental — accuracy not yet measuredEstrogen, specifically 17β-estradiol, promotes lipolysis and increases fatty acid availability while decreasing the rate of gluconeogenesis with muscle and liver glycogen sparing.
“Estrogen, specifically 17β-estradiol, promotes lipolysis and increases fatty acid availability while decreasing the rate of gluconeogenesis with muscle and liver glycogen sparing.”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [20]
The section “ERα and skeletal muscle fatty acid metabolism and inflammation” reports that estradiol enhances lipid oxidation and fatty-acid transport in muscle. It does not establish that estradiol promotes lipolysis or increases fatty-acid availability, and searches for gluconeogenesis and glycogen found no support for reduced gluconeogenesis or muscle and liver glycogen sparing. No page numbers were provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSignificant sex differences and sex hormone influences on carbohydrate and lipid metabolism are apparent.
“Significant sex differences and sex hormone influences on carbohydrate and lipid metabolism are apparent”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [20]
Important sex differences exist in mitochondrial function, substrate utilization, insulin sensitivity, immune responses, muscle morphology and body composition, iron metabolism, thermoregulation, hydration, appetite control, and energy availability and endocrine function.
“important sex differences exist in mitochondrial function [14–16], substrate utilization, and insulin sensitivity [17–24], immune responses [25–28], muscle morphology and body composition [29–32], iron metabolism [33–40], thermoregulation [41–44], hydration [45,46]{Sims, 2008 #55, [47–53], appetite control [54–59], and energy availability and endocrine function [60–65].”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [20]
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Sexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver
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Estrogenic control of mitochondrial function
Klinge, C. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101435 · Cited by 302 · see citing works
Menopause: a cardiometabolic transition
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Menopause—Biology, consequences, supportive care, and therapeutic options
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Functions of estrogen and estrogen receptor signaling on skeletal muscle
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Treating menopause — MHT and beyond
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Estrogens, Estrogen Receptors Effects on Cardiac and Skeletal Muscle Mitochondria
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International society of sports nutrition position stand: nutritional concerns of the female athlete
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“sensitivity as well as prevention of lipid accumulation and inflammation [20,21,67,68].”
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Hormonal regulation of metabolism—recent lessons learned from insulin and estrogen
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Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice
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Spaceflight induces changes in gene expression profiles linked to insulin and estrogen
Mathyk, B. A., Tabetah, M., Karim, R. S., Zaksas, V., Kim, J., I, A. R., Muratani, M., Tasoula, A., Singh, R. S., Chen, Y.-K., et al. (2024) · Communications Biology · doi:10.1038/s42003-023-05213-2 · Cited by 40 · see citing works
Key Roles of Brown, Subcutaneous, and Visceral Adipose Tissues in Obesity and Insulin Resistance
Dobre, M.-Z., Vîrgolici, B., & Timnea, O. C. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47050343 · Cited by 40 · see citing works
Wei, Y., Yuan, P., Zhang, Q., Fu, Y., Hou, Y. M., Gao, L., Zheng, X., & Feng, W. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05746-3 · Cited by 38 · see citing works
Fu, Q., Li, T., Zhang, C., Ma, X., Meng, L., Liu, L., Shao, K., Wu, G., Zhu, X., & Zhao, X. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01119-y · Cited by 30 · see citing works
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Ereqat, S., Cauchi, S., Eweidat, K., Elqadi, M., & Nasereddin, A. (2019) · PeerJ · doi:10.7717/peerj.7164 · Cited by 29 · see citing works
Penniman, C. M., Beltran, P. A. S., Bhardwaj, G., Junck, T. L., Jena, J., Poro, K., Hirshman, M. F., Goodyear, L. J., & O'Neill, B. T. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.10.001 · Cited by 27 · see citing works
Zhao, Z., Fan, X., Gu, Y., Han, J., Jia, Y., Ye, K., & Zhang, Y. Q. (2020) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101149 · Cited by 27 · see citing works
Adu‐Amankwaah, J., Bushi, A., Tan, R., Adekunle, A. O., Adzika, G. K., Noah, M. L. N., Nadeem, I., Adzraku, S. Y., Koda, S., Mprah, R., et al. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04886-6 · Cited by 26 · see citing works
Arcones, A. C., Cruces‐Sande, M., Ramos, P. S., Mayor, F., & Murga, C. (2019) · Cells · doi:10.3390/cells8111464 · Cited by 23 · see citing works
A human-based multi-gene signature enables quantitative drug repurposing for metabolic disease
Timmons, J. A., Anighoro, A., Brogan, R. J., Stahl, J., Wahlestedt, C., Farquhar, D. G., Taylor‐King, J. P., Volmar, C., Kraus, W. E., & Phillips, S. M. (2021) · eLife · doi:10.7554/elife.68832 · Cited by 21 · see citing works
Retinoic Acid: Sexually Dimorphic, Anti-Insulin and Concentration-Dependent Effects on Energy
Napoli, J. L. (2022) · Nutrients · doi:10.3390/nu14081553 · Cited by 15 · see citing works
Vignozzi, L., Malavolta, N., Villa, P., Mangili, G., Migliaccio, S., & Lello, S. (2018) · Journal of Endocrinological Investigation · doi:10.1007/s40618-018-0978-x · Cited by 14 · see citing works
Gender differences in GRK2 in cardiovascular diseases and its interactions with estrogen
Fu, L., Adu‐Amankwaah, J., Sang, L., Tang, Z., Gong, Z., Zhang, X., Li, T., & Sun, H. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00407.2022 · Cited by 14 · see citing works
Menstrual Cycle Tracking in Sports Research: Challenges, Progress, and Future Directions
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Ke, Z.-H., Li, Y., Yu, A., Cai, X.-F., Lin, Y., Lin, S.-H., Zheng, C., Yu, C.-X., Zheng, B., & Sun, Y. L. (2025) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2025.118791 · Cited by 11 · see citing works
Exercise as a therapeutic intervention for long-lasting and chronic diseases
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Wang, H., Zheng, A., Arias, E. B., Kwak, S. E., Pan, X., Duan, D., & Cartee, G. D. (2023) · The FASEB Journal · doi:10.1096/fj.202300282rr · Cited by 11 · see citing works
Retinoic acid exerts sexually dimorphic effects on muscle energy metabolism and function
Zhao, Y., Vuckovic, M. G., Yoo, H. S., Fox, N., Rodriguez, A., McKessy, K., & Napoli, J. L. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101101 · Cited by 11 · see citing works
Zhou, H., Feng, S., Cai, J., Shao, X., Zhu, S., Zhou, H., Cao, Y., Wang, R., Lin, X., & Wang, J. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70206 · Cited by 10 · see citing works
Ortiz-Huidobro, R. I., Larqué, C., Velasco, M., Chávez‐Maldonado, J. P., Sabido, J. R., Sánchez-Zamora, Y. I., & Hiriart, M. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00965-6 · Cited by 10 · see citing works
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Fuller, S. E., Yu, Y., Allerton, T. D., Mendoza, T. M., Ribnicky, D., & Floyd, Z. E. (2020) · Nutrients · doi:10.3390/nu12082233 · Cited by 9 · see citing works
Burman, A., García-Milian, R., & Whirledge, S. (2020) · Human Genomics · doi:10.1186/s40246-020-00269-1 · Cited by 9 · see citing works
Kothmann, K., Jacobsen, V., Laffitte, E., Bromfield, C. R., Grizzaffi, M., Jarboe, M., Braundmeier‐Fleming, A., Bahr, J. M., Nowak, R. A., & Newell‐Fugate, A. E. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00281.2020 · Cited by 9 · see citing works
Landen, S., Jacques, M., Hiam, D., Alvarez‐Romero, J., Harvey, N. R., Haupt, L. M., Griffiths, L. R., Ashton, K. J., Lamon, S., Voisin, S. A. C., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.16.435733 · Cited by 9 · see citing works
Estrogen in skeletal muscle: metabolism, mechanisms, and exercise-induced changes
Feng, Y., & Shi, R. (2025) · Journal of Endocrinological Investigation · doi:10.1007/s40618-025-02726-x · Cited by 8 · see citing works
Farhana, F., Sultana, M. A., Hia, R. A., & Hegde, V. K. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106501 · Cited by 7 · see citing works
Estrogen – serotonin interaction and its implication on insulin resistance
Ulhaq, Z. S. (2019) · Alexandria Journal of Medicine · doi:10.1080/20905068.2019.1670413 · Cited by 7 · see citing works
Incretins in the Therapy of Diabetic Kidney Disease
Przezak, A., Bielka, W., & Pawlik, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212312 · Cited by 7 · see citing works
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Metabolic Messengers: testosterone
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Sammut, M. J., McBey, D. P., Sayal, A. P., & Melling, C. W. J. (2024) · Journal of Diabetes Research · doi:10.1155/2024/5549762 · Cited by 5 · see citing works
Sex steroids, SHBG and type 2 diabetes in women: what do we really know?
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The role of estrogens in mitochondrial metabolism
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Midlife and the menopause transition in type 2 diabetes mellitus prevention
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- Authors
- Hevener, A. L., Zhou, Z., Moore, T. M., Drew, B. G., & Ribas, V.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Hevener, Andrea L.
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 15
- Pages
- 20-34
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC6066787
- OpenAlex
- W2808844109
- Cited by
- 72
- References
- 180
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 5 · 2023: 14 · 2022: 8 · 2021: 10 · 2020: 9 · 2019: 10 · 2018: 1
- FWCI
- 1.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (DK89109, DK063491)
- Jonsson Comprehensive Cancer Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- estrogen receptor alpha, skeletal muscle, muscle metabolism, insulin sensitivity, metabolic syndrome, menopause, sex differences, metabolic health, hormone replacement therapy, type 2 diabetes, adiposity
- MeSH terms
- Energy Metabolism, Female, Humans, Insulin Resistance, Male, Sex Characteristics, Exercise, Muscle, Skeletal, Estrogen Receptor alpha
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