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.

In female rats, the effects of TPM on fat and energy gains were clearly not influenced by the sex hormone status of the rats. In male animals, there was also no interaction of TPM and the status of sex hormones on energy balance, suggesting that OCX and testosterone minimally interfere with the action of TPM on energy balance. The effects of TPM on energy balance were accounted for by a decrease in energetic efficiency, resulting from an effect exerted by the drug on both energy intake and thermogenesis. The present results also suggest that TPM can enhance insulin sensitivity.

1 This study was undertaken to further investigate the eects of a sucrose-enriched diet on vascular function and insulin sensitivity in rats. 2 Male Sprague-Dawley rats were randomized to receive a sucrose-or regular rat chow-diet for 4 weeks. A ®rst group of sucrose-and chow-fed rats was instrumented with pulsed Doppler¯ow probes and intravascular catheters to determine blood pressure, heart rate, regional blood¯ows and insulin sensitivity in conscious rats. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique. Glucose transport activity was examined in isolated muscles by using the glucose analogue [ 3 H]-2-deoxy-D-glucose. A second group of sucrose-and chow-fed rats was used to obtain information regarding nitric oxide synthase (NOS) isozymes protein expression in muscles, and determine endothelin content in vascular tissues isolated from both dietary groups. 3 Sucrose feeding was found to induce insulin resistance, but had no eect on resting blood pressure, heart rate, or regional haemodynamics. This insulin resistance was accompanied by alteration in the vascular responses to insulin. Insulin-mediated skeletal muscle vasodilation was impaired, whereas the mesenteric vasoconstrictor response was potentiated in sucrose-fed rats. A reduction in eNOS protein content in muscle and an increase in vascular endothelin peptide were noted in these animals. Moreover, a reduction in insulin-simulated glucose transport activity was also noted in muscles isolated from sucrose-fed rats. 4 Together these data suggest that a cluster of metabolic and haemodynamic abnormalities occur in response to the intake of simple sugars in rats.

OBJECTIVE:The selective estrogen receptor (ER) modulator (SERM) acolbifene (ACOL), a potent and pure antiestrogen in the mammary gland and uterus, exerts beneficial pro-estrogenic actions on energy balance, insulin sensitivity and lipid metabolism. ACOL binds ERs a and b, both of which have been involved in the metabolic actions of estrogen. This study aimed at determining the identity of the ER involved in the beneficial metabolic actions of ACOL. DESIGN AND MEASUREMENTS: ACOL was administered for 4 weeks to male and female wild-type and ERa knockout (KO) mice, and indices of energy balance as well as plasma and liver lipid concentrations were determined. RESULTS: ERa KO mice were heavier, gained more fat mass and had larger adipose depots than their wild-type counterparts. In both genders, ACOL decreased fat gain (50%) and white adipose tissue mass in male and female wild-type, but not in ERa KO mice. ACOL reduced plasma cholesterol in female wild-type mice (À27%), whereas the compound remained ineffective in their ERa KO counterparts. Plasma triglycerides were unaffected by ACOL. Finally, ACOL decreased liver cholesterol and triglyceride concentrations only in wild-type female animals. CONCLUSION: The beneficial metabolic actions of the SERM ACOL on adiposity and on plasma and liver lipids are entirely due to its interaction with the ERa.

This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). Four weeks of treatment with ACOL reduced fasting and postprandial plasma triglycerides (TGs), an effect associated with lower VLDL-TG secretion rate ( ؊ 25%), and decreased mRNA of microsomal triglyceride transfer protein (MTP; ؊ 29%). ACOL increased liver TG concentration ( ؉ 100%) and amplified the feeding-induced increase in the master lipogenic regulators sterol-regulatory element binding protein-1a (SREBP-1a) and SREBP-1c. ACOL decreased total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and HMG-CoA reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals and correlated with plasma HDL-CHOL levels ( r ‫؍‬ 0.80, P Ͻ 0.002). Liver LDL receptor (LDLR) protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. This study demonstrates that ACOL possesses the unique ability among SERMs to reduce VLDL-TG secretion, likely by reducing MTP expression, and strongly suggests that the robust hypocholesterolemic action of ACOL is related to increased removal of CHOL from the circulation as a consequence of enhanced liver SR-BI and LDLR abundance. The concerns raised by the Women's Health Initiative Study regarding the health risks/benefits of hormone replacement therapy in postmenopausal women (1-3) strengthen the interest in evaluating the metabolic properties of other steroids as well as selective estrogen receptor modulators (SERMs) to improve the quality of life of this population. The estrogen antagonist acolbifene (ACOL; EM-652.HCl) is a SERM that was developed for the prevention and treatment of estrogen-sensitive cancers (4, 5). The compound behaves as a highly potent and pure antiestrogen in human breast and uterine cancer cells in vitro as well as in vivo in nude mice (4, 5). ACOL binds selectively to both the ␣ and ␤ types of estrogen receptors (6). Despite its pure antiestrogenic activity in the mammary gland and endometrium, ACOL can be classified as a SERM based on some estrogen-like properties, such as prevention of bone loss, decreasing plasma lipids (7-9), and reduction in body weight (mostly fat) gain (9, 10) in animal models. Therefore, ACOL shares actions on energy balance and lipemia with other steroids, such as various anticarcinogenic agents (11-15) and dehydroepiandrosterone (16)(17)(18)(19).One of the most striking actions of ACOL in rodent models is its robust hypolipidemic action. In rats, a triglyceride (TG)-lowering action has been reported in freely fed rats treated for 9 months with the ACOL prodrug EM-800 (8). Also, ACOL was found not to increase triglyceridemia, compared with estradiol treatment, in ovariectomized rats (10). Therefore, ACOL may beneficially affect triglyceridemia, at least under some conditions, an effect ...