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

Abstract

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.

The role of sex steroids in white adipose tissue adipocyte function

“…Although sex-and depot-related differences in ERα and ERβ have been reported (Pedersen et al 1991, Blouin et al 2009), E2-deficient mouse models indicate that E2 is important for lipid homeostasis and adipocyte lipolytic/lipogenic activity in both sexes (Heine et al 2000, Jones et al 2001. A study that administered a potent anti-estrogen, acolbifene, to mice demonstrated that both males and females developed decreased WAT mass and circulating cholesterol (Lemieux et al 2005). Although studies in rodents support similar WAT responses in males and females to direct E2 stimulation at classical ERs (Heine et al 2000, Jones et al 2001, other evidence supports a heterogenous response to E2, particularly in the context of obesity.…”

Resistance training restores the gene expression of molecules related to fat oxidation and lipogenesis in the liver of ovariectomized rats

“…Ovariectomized (OVX) rats, as well as aromatase, and estrogen receptor knockout mice develop nonalcoholic fatty liver disease (NAFLD), which is characterized by triglyceride accumulation in hepatocytes (hepatic steatosis) (Lemieux et al 2005), one of the most frequent causes of abnormal liver function (Angulo 2002;Browning and Horton 2004). In a recent study that included over 800 women aged 40-59 years, it was confirmed that the menopausal status was indeed associated with hepatic steatosis (Volzke et al 2007).…”

Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat

“…Although men with ER ␣ mutation developed severe steatosis ( 7 ), the three adult men reported with aromatase defi ciency had impaired lipid metabolism, and only one presented with hepatic steatosis ( 8 ). Aromataseknockout mice ( 3,4 ), ER ␣ -knockout ( ␣ ERKO) mice ( 9 ), and the double ER ␣ and ␤ knockout mice ( 10 ) display elevated triglyceride (TG) levels ( 11 ). These clinical and experimental studies have shown the signifi cant role of the estrogen signaling pathway in lipid homeostasis ( 3,4 ).…”

“…6A ). In this de novo lipogenesis by [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C-labeling acetic acid procedure, we traced the total radiation that can refl ect the lipogenesis. Acetate is the precursor of lipid synthesis, and fatty acid is the substrate of sterols and lipid synthesis.…”