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 and pure antiestrogen in human breast and uterine cancer cells. Because of its 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 receptor modulator (SERM). This study was conducted to assess the ability of EM-652.HCl to prevent obesity and abnormalities of lipid metabolism induced by ovariectomy in a rat model.


METHODS
Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E2), or EM-652.HCl for 20 days. At the end of the treatment period, parameters of energy balance and determinants of lipid metabolism were assessed.


RESULTS
As expected, OVX increased energy intake, which in turn was accompanied by an increased energy, fat and protein gain and higher food efficiency. OVX also increased the triglyceride content of the liver and produced hypercholesterolemia and hyperinsulinemia. The weight of representative white 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 intact animals, whereas its activity was lower in oxidative tissues (brown adipose and soleus muscle). Replacement therapy with a physiological dose of E2 prevented most of the abnormalities in energy and lipid metabolism brought about by OVX, although its orexigenic effect was only partially corrected. In contrast, treatment of OVX rats with EM-652. HCl completely abolished OVX-induced obesity and its related abnormalities in lipid metabolism and glucose/insulin homeostasis.


CONCLUSIONS
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 obesity such as hyperlipidemia and insulin resistance.
Picard
F
F
Center for Research on Energy Metabolism, Department of Anatomy and Physiology, School of Medicine, Laval University, Québec, Canada G1K 7P4.
Deshaies
Y
Y
Lalonde
J
J
Samson
P
P
Labrie
C
C
Bélanger
A
A
Labrie
F
F
Richard
D
D
D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D004965:Estrogen Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006949:Hyperlipidemias / Q000150:complications / Q000517:prevention & control; D007333:Insulin Resistance; D050356:Lipid Metabolism; D009765:Obesity / Q000209:etiology / Q000517:prevention & control*; D010052:Ovariectomy / Q000009:adverse effects*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology* / Q000627:therapeutic use
D004965:Estrogen Antagonists; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; C012121:ritetronium