The estrogen antagonist EM-652 and dehydroepiandrosterone prevent diet- and ovariectomy-induced obesity.
OBJECTIVE
EM-652 is a pure antiestrogen in human breast and uterine cancer cells that also reduces bone loss and plasma lipid levels in the rat. This study aimed to assess the ability of EM-652, alone or with dehydroepiandrosterone (DHEA), to prevent obesity and related metabolic abnormalities induced by an obesity-promoting diet and ovariectomy.


METHODS
Female rats were fed a high-sucrose, high-fat (HSHF) diet, were left intact or ovariectomized (OVX), and were treated with EM-652, DHEA, or both for 20 days. Variables of energy balance and determinants of lipid metabolism and insulin sensitivity were assessed.


RESULTS
The HSHF diet (vs. chow) and OVX both increased energy intake and gain, as well as energetic efficiency. Both EM-652 and DHEA prevented diet- and OVX-induced energy gain mainly by decreasing fat deposition, without being additive. The modest EM-652-induced increase in liver triglycerides of intact rats was prevented by its combination with DHEA. EM-652, but not DHEA, decreased cholesterolemia. The HSHF diet and OVX reduced insulin sensitivity, an effect that was attenuated by EM-652 and abrogated by DHEA and EM-652+DHEA. Treatment with EM-652, DHEA, or their combination abolished the diet- and OVX-induced increase in adipose lipoprotein lipase activity that accompanied fat gain.


CONCLUSIONS
EM-652 is an effective agent to prevent diet- and OVX-induced obesity and its associated cardiovascular risk factors such as insulin resistance. The addition of DHEA prevents hepatic lipid accumulation and further ameliorates insulin sensitivity. The beneficial metabolic effects of such combined steroid therapy may, therefore, eventually prove to be clinically relevant.
Lemieux
Christian
C
Centre de Recherche de l'Hôpital Laval and Département d'Anatomie et Physiologie, Faculté de Médecine, Université Laval, Quebec, Canada.
Picard
Frédéric
F
Labrie
Fernand
F
Richard
Denis
D
Deshaies
Yves
Y
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D002784:Cholesterol / Q000097:blood; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000627:therapeutic use*; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage; D019422:Dietary Sucrose / Q000008:administration & dosage; D004435:Eating; D002149:Energy Intake; D004734:Energy Metabolism; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D007333:Insulin Resistance; D008071:Lipoprotein Lipase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000209:etiology* / Q000517:prevention & control*; D010052:Ovariectomy; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain
D004041:Dietary Fats; D019422:Dietary Sucrose; D004965:Estrogen Antagonists; D010880:Piperidines; D014280:Triglycerides; C012121:ritetronium; D003687:Dehydroepiandrosterone; D002784:Cholesterol; D008071:Lipoprotein Lipase