Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice.

The Journal of biological chemistry

PubMedID: 20657011

Yepuru M, Eswaraka J, Kearbey JD, Barrett CM, Raghow S, Veverka KA, Miller DD, Dalton JT, Narayanan R. Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice. J Biol Chem. 2010;285(41):31292-303.
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) ß as an important regulator of metabolic diseases. However, the potential of ER-ß-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-ß-selective ligands (ß-LGNDs) in animal models of high-fat diet- and ovariectomy-induced obesity. Ligand binding, transactivation, and uterotrophic studies with ß-LGNDs demonstrated selectivity for ER-ß over ER-a. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by ß-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by ß-LGNDs. In addition, MRI scanning indicated that ß-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 ß-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 ß-LGNDs were due to indirect peroxisome proliferator-activated receptor ? antagonistic actions requiring the ligand binding domain of ER-ß and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor ?. In conclusion, these studies indicate that ligand-activated ER-ß is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.