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Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice
Open accessAbstract
Obesity is an epidemic problem affecting millions of people in the Western hemisphere and costs the United States economy more than $200 billion annually. Currently, there are no effective treatments to combat obesity. Recent studies have implicated the constitutive activity of estrogen receptor (ER) β as an important regulator of metabolic diseases. However, the potential of ER-β-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-β-selective ligands (β-LGNDs) in animal models of high-fat diet- and ovariectomy-induced obesity. Ligand binding, transactivation, and uterotrophic studies with β-LGNDs demonstrated selectivity for ER-β over ER-α. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by β-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by β-LGNDs. In addition, MRI scanning indicated that β-LGNDs altered body composition by reducing fat mass and increasing lean body mass. Organ weights and gene expression analyses demonstrated that adipose tissue is the center of action for β-LGNDs, and the reduction in body weight is likely due to increased energy expenditure. In vitro and in vivo mechanistic studies indicated that the anti-obesity effects of β-LGNDs were due to indirect peroxisome proliferator-activated receptor γ antagonistic actions requiring the ligand binding domain of ER-β and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor γ. In conclusion, these studies indicate that ligand-activated ER-β is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.
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“Despite the absence of any reported changes in fat deposition in global ERβ KO mice, agonistic ERβ‐selective ligands have been reported to mitigate diet‐induced obesity in male mice.”
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 [213]
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Metadata
- Authors
- Yepuru, M., Eswaraka, J., Kearbey, J. D., Barrett, C. M., Raghow, S., Veverka, K. A., Miller, D. D., Dalton, J. T., & Narayanan, R.
- Affiliations
- GTx (United States) (US)
- Corresponding author
- Dalton, James T.
- Narayanan, Ramesh
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 285
- Issue
- 41
- Pages
- 31292-31303
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2951204
- OpenAlex
- W2081999578
- Cited by
- 125
- References
- 73
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 3 · 2023: 8 · 2022: 12 · 2021: 6 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 15 · 2016: 8 · 2015: 11 · 2014: 7 · 2013: 12 · 2012: 5
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- estrogen receptor beta, obesity, high-fat diet, ovariectomy, adipose tissue, energy expenditure, body composition, metabolic disorders, ligand-binding domain, leptin, serum cholesterol
- MeSH terms
- Animals, Blood Glucose, Cholesterol, Dietary Fats, Disease Models, Animal, Female, Isoquinolines, Ligands, Male, Obesity, Organ Size, Ovariectomy, Transcription Factors, Rats, Sprague-Dawley, Leptin, PPAR gamma, Estrogen Receptor beta, Mice, Rats
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