Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice.
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.
Yepuru
Muralimohan
M
Preclinical Research and Development, GTx Inc, Memphis, Tennessee 38163, USA.
Eswaraka
Jeetendra
J
Kearbey
Jeffrey D
JD
Barrett
Christina M
CM
Raghow
Sharan
S
Veverka
Karen A
KA
Miller
Duane D
DD
Dalton
James T
JT
Narayanan
Ramesh
R
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000378:metabolism; D005260:Female; D007546:Isoquinolines / Q000494:pharmacology*; D020738:Leptin / Q000097:blood; D008024:Ligands; D008297:Male; D051379:Mice; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D009929:Organ Size; D010052:Ovariectomy; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism
D001786:Blood Glucose; D004041:Dietary Fats; D047629:Estrogen Receptor beta; D007546:Isoquinolines; D020738:Leptin; D008024:Ligands; D047495:PPAR gamma; D014157:Transcription Factors; C585485:beta-LGND2; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D002784:Cholesterol