Estrogen receptor-β-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice

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

Research output: Contribution to journalArticle

72 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)31292-31303
Number of pages12
JournalJournal of Biological Chemistry
Volume285
Issue number41
DOIs
StatePublished - Oct 8 2010

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High Fat Diet
Ovariectomy
Nutrition
Estrogen Receptors
Obesity
Fats
Ligands
Peroxisome Proliferator-Activated Receptors
Metabolic Diseases
Animals
Body Weight
Organ Size
Leptin
Body Composition
Gene expression
Magnetic resonance imaging
Energy Metabolism
Transcriptional Activation
Weight Gain
Adipose Tissue

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Estrogen receptor-β-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice. / Yepuru, Muralimohan; Eswaraka, Jeetendra; Kearbey, Jeffrey D.; Barrett, Christina M.; Raghow, Sharan; Veverka, Karen A.; Miller, Duane; Dalton, James T.; Narayanan, Ramesh.

In: Journal of Biological Chemistry, Vol. 285, No. 41, 08.10.2010, p. 31292-31303.

Research output: Contribution to journalArticle

Yepuru, Muralimohan ; Eswaraka, Jeetendra ; Kearbey, Jeffrey D. ; Barrett, Christina M. ; Raghow, Sharan ; Veverka, Karen A. ; Miller, Duane ; Dalton, James T. ; Narayanan, Ramesh. / Estrogen receptor-β-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 41. pp. 31292-31303.
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