Cited by 125Estrogen and related hormone effectsPeroxisome Proliferator-Activated ReceptorsRegulation of Appetite and Obesity

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Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

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Yepuru, Muralimohan, Eswaraka, Jeetendra, Kearbey, Jeffrey D., Barrett, Christina M., Raghow, Sharan, Veverka, Karen A., Miller, Duane D., Dalton, James T., Narayanan, Ramesh·2010·Journal of Biological Chemistry

DOI 10.1074/jbc.m110.147850PMC PMC2951204

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Abstract

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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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
ORCID: Veverka, Karen A.
Miller, Duane D.
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)
DOI: 10.1074/jbc.m110.147850
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 3664 d)
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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Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

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