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

Abstract

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 classi®ed 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. DESIGN: Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E 2 ), 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 ef®ciency. 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 E 2 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 glucoseainsulin homeostasis. CONCLUSION: These ®ndings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVXinduced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with obesity such as hyperlipidemia and insulin resistance.

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

“…We have previously observed in the rat a very strong (-50%) cholesterol-lowering action of ACOL. [14][15][16] The milder hypocholesterolemic action of ACOL in the present study is not surprising given that mice are generally more resistant to interventions aimed at reducing cholesterolemia. 27,28 ACOL therefore shares the ability to decrease plasma cholesterol, an estrogen-like effect, with other SERMs such as tamoxifene, 29 raloxifene, 30 tibolone 31 and miproxifene phosphate 32 that have been studied in various animal models.…”

“…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.…”

“…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.…”

“…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.…”