The Estrogen Antagonist EM‐652 and Dehydroepiandrosterone Prevent Diet‐ and Ovariectomy‐Induced Obesity

Abstract

LEMIEUX, CHRISTIAN, FRÉ DÉ RIC PICARD, FERNAND LABRIE, DENIS RICHARD, AND YVES DESHAIES.The estrogen antagonist EM-652 and dehydroepiandrosterone prevent diet-and ovariectomy-induced obesity. Obes Res. 2003;11:477-490. 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. Research Methods and Procedures: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 OVXinduced 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-652ϩDHEA. Treatment with EM-652, DHEA, or their combination abolished the diet-and OVX-induced increase in adipose lipoprotein lipase activity that accompanied fat gain. Discussion: EM-652 is an effective agent to prevent dietand 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.

Estrogen receptor α-mediated adiposity-lowering and hypocholesterolemic actions of the selective estrogen receptor modulator acolbifene

“…This estrogen-like effect of the SERM confirms previous findings in intact and ovariectomized rats, in which ACOL treatment was shown to reduce markedly weight (mainly fat) accretion. [14][15][16] In both Acolbifene in ERa KO mouse C Lemieux et al female and male ERa KO mice, ACOL was unable to prevent weight and fat gain, and even tended to increase weight gain in female mice. This finding establishes that the lowering action of ACOL on weight gain is mediated via an interaction with the ERa.…”

“…15,16 This anorectic action of ACOL is akin to that of natural estrogen, which has been shown in numerous studies to decrease food intake in rats. 22,23 In the present study however, despite a transient initial reduction in food consumption, cumulative food intake of female and male wild-type mice was not greatly affected by ACOL treatment.…”

“…They were then fed ad libitum a purified high carbohydrate diet that contained, in g/100 g diet: starch, 31 KO), and drug treatment (placebo and ACOL), with eight to 10 animals per group. As described previously, 16 ACOL (EM-652.HCL) was given once daily at 0800 by oral gavage in a methylcellulose suspension at a dose of 2.5 mg/kg/day in a total volume of 0.2 ml. The control group received the same volume of vehicle alone.…”

“…14 We have previously demonstrated beneficial changes in body weight and the lipid profile of female rats following chronic treatment with the fourth-generation SERM Acolbifene (ACOL). 15,16 The drug was shown in rats to decrease greatly body weight gain, mostly fat mass, mainly through a reduction in food intake. ACOL also increased insulin sensitivity and brought about a major decrease in plasma cholesterol.…”

“…ACOL also increased insulin sensitivity and brought about a major decrease in plasma cholesterol. 15,16 The SERM binds to both ERa and ERb with much higher affinity than estrogen. 14 Given this and the above-mentioned uncertainties that remain regarding the respective involvement of ERa and ERb in the modulation of energy balance and lipid metabolism, the present study was designed to determine whether the metabolic actions of ACOL were solely due to its interaction with the ERs, and if so, to establish the identity of the receptor.…”