Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice
Open accessAbstract
In addition to its role in reproduction, estradiol-17β is critical to the regulation of energy balance and body weight. Estrogen receptor α-null (Erα-/-) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERα signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERα that can only signal through the noncanonical pathway to assess the role of nonclassical ERα signaling in energy homeostasis. In these mice, we found that nonclassical ERα signaling restored metabolic parameters dysregulated in Erα-/- mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERα signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERα signaling mediates major effects of estradiol-17β on energy balance, raising the possibility that selective ERα agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women.
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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 [144]
The Body weight, adiposity, and food intake section (page unavailable) reports greater weight and body fat in female Erα-knockout mice. The same section reports elevated blood glucose after glucose and insulin challenges in knockout mice. The copy does not establish these findings in males, so it does not support the claim’s “both males and females” qualifier. (LLM, conf=0.88)
Experimental — accuracy not yet measuredERα plays a major role in adipocyte activity and sexual dimorphism of fat distribution.
“ERα plays a major role in the activity of adipocytes and sexual dimorphism of fat distribution.”
From Estrogen deficiency and the origin of obesity during menopause (2014) · cites this paper as [63]
Female and male mice lacking ERα have central obesity, severe insulin resistance, and are diabetic.
“Female and male mice that lack ERα have central obesity, have severe insulin resistance, and are diabetic [63–65].”
From Estrogen deficiency and the origin of obesity during menopause (2014) · cites this paper as [63]
Male ERα KO mice have increased fat mass; while in contrast, ERβ KO mice exhibit no fat phenotype.
“Male ERα KO mice have increased fat mass 204 , 205 , 206 , 207 ; while in contrast, ER β KO mice exhibit no fat phenotype, 207 , 208 , 209”
From The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments (2022) · cites this paper as [204]
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References 60 · Cited by 162
Research works printed but not linked: 2
- Yokosuka M, Okamura H, Hayashi S. Postnatal development and sex difference in neurons contain- ing estrogen receptor-alpha immunoreactivity in the preoptic brain, the diencephalon, and the amyg- dala in the rat. J Comp Neurol. 1997;389(1):81-93.
- Shughrue PJ, Lane MV, Merchenthaler I. Compara- tive distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol. 1997;388(4):507-525.
- Authors
- Park, C. J., Zhao, Z., Glidewell-Kenney, C., Lazic, M., Chambon, P., Krust, A., Weiss, J., Clegg, D. J., Dunaif, A., Jameson, J. L., & Levine, J. E.
- Affiliations
- Northwestern University (US)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Levine, Jon E.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2011-02-01
- Volume
- 121
- Issue
- 2
- Pages
- 604-612
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3026715
- OpenAlex
- W2071542414
- Cited by
- 162
- References
- 60
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 2 · 2023: 9 · 2022: 10 · 2021: 6 · 2020: 6 · 2019: 12 · 2018: 18 · 2017: 15 · 2016: 9 · 2015: 13 · 2014: 11 · 2013: 14 · 2012: 18
- FWCI
- 9.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- univOAK (4 institutions : Université de Strasbourg, Université de Haute Alsace, INSA Strasbourg, Bibliothèque Nationale et Universitaire de Strasbourg) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Child Health and Human Development
- National Center for Research Resources (M01RR000048)
- Office of Research on Women's Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50 HD44405, P50HD044405, P01HD021921, P01HD21921)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- estrogen receptor alpha, energy balance, obesity, energy expenditure, locomotor activity, estradiol, leptin, glucose homeostasis, postmenopausal obesity, type 2 diabetes
- MeSH terms
- Animals, Body Weight, Eating, Energy Metabolism, Female, Homeostasis, Humans, Mice, Obese, Motor Activity, Obesity, Signal Transduction, Mice, Knockout, Leptin, Estrogen Receptor alpha, STAT3 Transcription Factor, Mice
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