Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats

OBJECTIVE: The estrogen antagonist EM-652.HCl behaves as a highly potent an d pure antiestrogen in human breast and uterine cancer cells. Because of it s pure antiestrogenic activity in these cells, and because its prodrug, EM- 800, reduces bone loss and decreases serum cholesterol and triglycerides in the rat, EM-652.HCl can be classified as a pure selective estrogen recepto r modulator (SERM). This study was conducted to assess the ability of EM-65 2.HCl to prevent obesity and abnormalities of lipid metabolism induced by o variectomy in a rat model. DESIGN: Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E-2), or EM-652.HCl far 20 days. At t he end of the treatment period, parameters of energy balance and determinan ts of lipid metabolism were assessed. RESULTS: As expected, OVX increased energy intake, which in turn was accomp anied by an increased energy, fat and protein gain and higher food efficien cy. OVX also increased the triglyceride content of the liver and produced h ypercholesterolemia and hyperinsulinemia. The weight of representative whit e adipose depots was higher in OVX than in intact rats. Lipoprotein lipase activity was higher in white adipose tissues of OVX rats than in those of i ntact animals, whereas its activity was lower in oxidative tissues (brown a dipose and soleus muscle). Replacement therapy with a physiological dose of E-2 prevented most of the abnormalities in energy and lipid metabolism bro ught about by OVX, although its orexigenic effect was only partially correc ted. In contrast, treatment of OVX rats with EM-652.HCl completely abolishe d OVX-induced obesity and its related abnormalities in lipid metabolism and glucose/insulin homeostasis. CONCLUSION: These findings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVX-induced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with o besity such as hyperlipidemia and insulin resistance.