Biochimie xxx (2015) 1e6

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Review

Effect of selective estrogen receptor modulators on metabolic homeostasis Beibei Xu, Dragana Lovre, Franck Mauvais-Jarvis* Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 April 2015 Accepted 24 June 2015 Available online xxx

Selective estrogen receptor modulators (SERMs) are estrogen receptor (ER) ligands that exhibit either estrogen agonistic or antagonistic activity in a tissue-specific manner. The first and second generation SERMs, tamoxifen and raloxifene, are used for treatment of ER positive breast cancer and postmenopausal osteoporosis respectively. The third-generation SERM, bazedoxifene (BZA), effectively prevents osteoporosis while blocking the estrogenic stimulation in breast and uterus. Notably, BZA combined with conjugated estrogens (CE) in a tissue-selective estrogen complex (TSEC) is a new menopausal treatment. Postmenopausal estrogen deficiency predisposes to metabolic syndrome and type 2 diabetes, and therefore the effects of SERMs and TSECs on metabolic homeostasis are gaining attention. In this article, we summarize current knowledge about the impact of SERMs on metabolic homeostasis and metabolic disorders in animal models and postmenopausal women. © 2015 Published by Elsevier B.V.

Keywords: Selective estrogen receptor modulators Tissue-selective estrogen complex Bazedoxifene Metabolic syndrome Energy metabolism Diabetes

1. Introduction Following the increase in longevity in developed countries, most women will spend the second half of their lives in a state of estrogen deficiency. In addition to predisposing to cardiovascular, skeletal and neurodegenerative diseases, estrogen deficiency enhances metabolic dysfunction predisposing to obesity, metabolic syndrome and type 2 diabetes (T2D). Thus the contribution of estrogen deficiency in the pathobiology of metabolic diseases in women is emerging as a new therapeutic challenge. In that context, we need to harness the beneficial properties of estrogen on metabolic homeostasis while also avoiding its side effects on reproductive tissues.

Abbreviations: SERMs, selective estrogen receptor modulators; ER, estrogen receptor; BZA, bazedoxifene; CE, conjugated estrogens; TSEC, tissue-selective estrogen complex; T2D, type 2 diabetes; DMBA, 7, 12-dimethylbenz[a]anthracene; HDL, high-density lipoprotein; LDL, low-density lipoprotein; STZ, streptozotocin; FAS, fatty acid synthase; Mmd2, monocyte to macrophage differentiationassociated 2; Lcn13, lipocalin 13; PPARg, peroxisome proliferator-activated receptor gamma; FGF21, fibroblast growth factor-21; SIRT1, sirtuin1; PPARa, peroxisome proliferator-activated receptor a; AMPKa, AMP-activated protein kinase a; OVX, ovariectomized. * Corresponding author. Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, 1430 Tulane Ave SL-53, New Orleans, LA 70112, USA. E-mail address: [email protected] (F. Mauvais-Jarvis).

Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrogen receptors (ERs) as ER ligands and induce a unique ER conformation that correlates with different behaviors in estrogen-responsive tissue. SERMs exert agonist or antagonist effects on ER in a tissue-specific pattern due to the complexity of ER signaling, including different tissue distribution of ER receptors [1], ligand binding specificity [2,3] and diverse interactions with coactivators or corepressors [4,5]. Tamoxifen, one of the first generation of SERMs, behaves as an estrogen receptor antagonist in breast tissue and is used to prevent and treat estrogen receptor-positive (ER-positive) breast cancer [6]. However, tamoxifen acts as an estrogen receptor agonist in the uterine endometrium which increases endometrial carcinoma risk [7,8]. The second-generation SERMs were developed to overcome the adverse effect of tamoxifen on endometrial proliferation. Raloxifene, which retains anti-estrogenic activity in breast tissue [9] and exhibits estrogenic activity in bone, can also prevent osteoporosis [10]. The emerging third-generation SERM, bazedoxifene (BZA), is used to prevent osteoporosis in postmenopausal women without raising the safety concerns related to endometrium and breast tissue [11,12]. The combination of bazedoxifene with conjugated estrogen (CE) in a tissue-selective estrogen complex (TSEC) is now approved for menopausal therapy [13]. In addition to the well-known effects of SERMs on breast, bone and endometrium, the impact of SERMs on metabolic homeostasis and metabolic disease are gaining more attention. In this article, we

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summarize current knowledge about the impacts of SERMs on metabolic homeostasis and metabolic disorders in animal models and postmenopausal women.

2. The effects of tamoxifen on metabolism Tamoxifen has been used for over 40 years to treat ER-positive breast cancer due to its anti-estrogenic effect on breast tissue [2]. It has been gradually recognized that tamoxifen causes metabolic side effects, such as diabetes, lipid abnormities and hepatic steatosis (Table 1). Independent population-based studies were conducted in women with breast cancer and revealed a significant correlation between tamoxifen treatment and an increased incidence of diabetes [14e16]. In premenopausal women at high risk of breast cancer, treatment with tamoxifen did not alter fasting blood glucose levels or insulin sensitivity (evaluated with HOMA index) compared to placebo [17]. However, in a subgroup of overweight women, insulin sensitivity decreased dramatically in patients taking tamoxifen compared to those on placebo [17]. The underlying mechanism by which tamoxifen increases insulin resistance remains poorly understood but could involve the development of hepatic steatosis, as will be discussed below. Interestingly, in wildtype female mice, tamoxifen reversed the protective effect of estradiol on preventing insulin-deficient diabetes induced by streptozotocin (STZ), suggesting that tamoxifen acts as an ER antagonist in pancreatic b cells and may have adverse action in pancreatic islets [18]. Hypertriglyceridemia is a frequently encountered lipid abnormality in patients with uncontrolled diabetes [19]. Tamoxifen treatment caused severe hypertriglyceridemia in both breast cancer patients with preexisting diabetes [20,21] and those with no

history of diabetes [22,23], indicating that tamoxifen usage exacerbates lipid abnormalities. Tamoxifen treatment promotes the development of nonalcoholic fatty liver (hepatic steatosis) in women with breast cancer [24e27]. The occurrence of fatty liver in women with breast cancer was observed as early as 3 months following the initiation of tamoxifen treatment [24]. In healthy women who had a hysterectomy, tamoxifen treatment was associated with higher risk of development of non-alcoholic steatohepatitis only in overweight and obese women with features of metabolic syndrome [28]. The mechanisms by which tamoxifen promotes fatty liver were explored in rodent models [29e31]. In a rat mammary tumor model induced by 7, 12-dimethylbenz[a]anthracene (DMBA), tamoxifen treatment increased the synthesis of triglyceride in the liver without affecting fatty acid b-oxidation, resulting in elevated liver triglyceride content [29]. Another report found that tamoxifen treatment increased de novo fatty acid synthesis in mouse liver, which was achieved at least partially through downregulating the activity of AMPK kinase, a master activator of fatty acid oxidation and suppressor of fatty acid synthesis [30]. The inhibition of fatty acid b-oxidation was not observed in this study. In male Wistar rats receiving tamoxifen, fatty liver was caused by decreased expression and enzyme activity of fatty acid synthase (FAS). This resulted in the accumulation of the FAS substrate malonyl-CoA, leading to impaired fatty acid b-oxidation and hepatic triglyceride accumulation [31]. Furthermore, consistent with in vivo findings, tamoxifen treatment of HepG2 cells cultured in medium containing oleic acid or very low density lipoprotein directly increased intracellular triglyceride concentration [32]. Several studies conducted in rodents also suggested that tamoxifen could also have a neutral or even protective effect on fatty liver. For example, the impact of tamoxifen on steatosis was neutral in the absence of high fat diet in male SpragueeDawley (SD) rats [33]. In female ICR mice with hepatic

Table 1 Impacts of tamoxifen on metabolism.

Tamoxifen

Diabetes Fasting blood glucose Insulin sensitivity

Results

Study subjects

Increased diabetes incidence [14e16] Reversed protective effect of estrogen on STZ-induced diabetes [18] Unchanged [17]

Women with breast cancer Wild-type female mice Premenopausal women at high risk of breast cancer

Unchanged [17] Decreased 7 times compared to placebo group [17]

Premenopausal women at high risk of breast cancer Overweight premenopausal women at high risk of breast cancer Breast cancer patients with diabetes [20,21] Breast cancer patients without diabetes [22,23] Breast cancer patients [24e27] Overweight healthy women who had a hysterectomy with features of metabolic syndrome [28] Rat mammary tumor model induced by DMBA

Lipid profile

Hypertriglyceridemia [20e23]

Steatosis

[

[

Weight gain and obesity

Increased incidence of fatty liver [24e28]

Elevated liver triglyceride level due to increased synthesis of triglyceride [29] [ Increased de novo fatty acid synthesis through decreased AMPK kinase activity [30] [ Impaired fatty acid b-oxidation and hepatic triglyceride accumulation [31] [ Increased intracellular triglyceride concentration [32] e No effect on steatosis in the absence of high fat diet [33] Y Diminished inflammatory responses [34] Y Upregulated hepatic Mmd2 mRNA [35] Y Upregulated expression of two fatty acid b-oxidation key regulator in the liver, Lcn13 and PPARg [36] Decreased food intake, body weight and body fat content [37] Suppressed weight gain although it was not achieved only via suppression of food intake [38] Higher serum leptin level [40] Higher serum leptin level in patients who developed fatty liver during short-term (3 month) tamoxifen treatment than those without fatty liver [41] Lower weight gain in obese women (free of cancer) [42] Lower weight gain and decreased food intake in rats receiving tamoxifen [42]

Male C57BL/6 Pemt

/

mice

Male Wistar rats HepG2 cells Male SpragueeDawley rats Female ICR mice Female ICR mice Female WSB/EiJ mice Ovariectomized rats Neutered female Wistar-Kyoto rats Breast cancer patients Breast cancer patients Women with a family history of breast cancer Wistar rats

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steatosis induced by high fat diet or methionine and choline deficient diet, tamoxifen administration alleviated hepatic steatosis due to diminished inflammatory responses [34]. Another report found that tamoxifen played a hepatoprotective role against hepatotoxic compounds via hepatic induction of monocyte to macrophage differentiation-associated 2 (Mmd2) in an ERa dependent manner [35]. Finally, in female WSB/EiJ mice, tamoxifen treatment upregulated two key regulators of hepatic fatty acid b-oxidation, namely lipocalin 13 (Lcn13) and the peroxisome proliferatoractivated receptor gamma (PPARg) [36]. The effect of tamoxifen on food intake and body weight control is noteworthy. In ovariectomized female rats, tamoxifen led to decreased food intake, and reduced body fat and body weight [37]. Similarly, tamoxifen suppressed weight gain in neutered female Wistar-Kyoto (WKY) rats, although it was not achieved only via suppression of food intake [38]. Leptin is a key regulator of energy balance and serum leptin level positively correlates with body fat mass [39]. Therefore, measuring serum leptin levels is an approach to evaluate the effect of tamoxifen on weight gain and obesity. In patients with breast cancer receiving tamoxifen, serum leptin levels were higher than those in patients not taking tamoxifen [40]. Another study compared serum leptin level among breast cancer patients receiving short-term (3-month) tamoxifen treatment [41]. In these patients, increased serum leptin levels were observed only in patients who developed fatty liver. In contrast, tamoxifen seems to decrease body weight among women without cancer [42]. Weight gain (assessed by BMI increase) was lower in obese women taking tamoxifen compared to those taking placebo, suggesting an anorectic effect of tamoxifen, which has also been shown in rats. The mechanism involved a decrease in the FAS mRNA expression, which caused the accumulation of malonyl-CoA in the ventromedial nucleus of the hypothalamus [42]. Thus, the effect of tamoxifen on energy balance, which could involve ER agonist activity in the hypothalamus, should be investigated in further studies. 3. The effects of raloxifene on metabolism Raloxifene is as effective as tamoxifen in lowering the risk of invasive breast cancer [43]. It also has a beneficial effect on preventing postmenopausal osteoporosis as an ER agonist in bone [10]. Raloxifene is not as adverse as tamoxifen on metabolism and its effects on metabolic homeostasis are summarized as follows (Table 2). Raloxifene inhibited estrogen deficiency-induced weight gain in ovariectomized female rats [44,45]. In healthy postmemopausal women, raloxifene treatment for one year prevented body weight gain and abdominal adiposity by promoting a shift from an android to gynoid fat distribution [46]. In another 12-month-long study, although raloxifene failed to affect body weight in postmenopausal women, it significantly altered body composition by increasing fatfree mass and total body water [47]. However, six months of raloxifene treatment did not enhance exercise-induced weight loss or fat-mass loss in postmenopausal women [48], which may be explained by its effect on elevating fat-free mass and total body water. Whether raloxifene modifies fasting blood glucose and insulin levels has been investigated based on the duration of treatment. In postmenopausal women with or without type 2 diabetes, shortterm raloxifene treatment (12 weeks or 6 months) did not alter fasting blood glucose [49e52] or insulin level [49,50,52] and had no effect on glucose tolerance [49,50] or insulin sensitivity [50e52]. Notably, in a subgroup of patients with hyperinsulinemia, raloxifene significantly reduced plasma insulin by improving fractional hepatic extraction of insulin and peripheral insulin sensitivity [49]. Similar to short-term treatment, long-term raloxifene treatment

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(12 months) did not modify fasting glucose or glucose tolerance [53]. However, in contrast to short-term treatment, long-term raloxifene treatment decreased insulin sensitivity [53]. This may need further investigation since the number of study subjects in this report was small (only 24 patients). It is known that estrogen can increase the concentration of highdensity lipoprotein (HDL) cholesterol (the “good” cholesterol) while decreasing the concentration of low-density lipoprotein cholesterol (LDL) (the “bad” cholesterol) in the blood of healthy postmenopausal women [54]. On the other hand, estrogen can increase triglyceride levels, which may lead to hypertriglyceridemia [54]. The impact of raloxifene on serum lipids profile has been explored in postmenopausal women in multiple clinical studies. Like estrogen, raloxifene significantly decreased LDL cholesterol level [50,51,53,55]. However, unlike estrogen, raloxifene did not change HDL cholesterol [50,51] or triglyceride levels [50,51,56] regardless of the duration of treatment. Even in patients with a history of oral estrogen-induced hypertriglyceridemia, raloxifene did not exacerbate triglyceride levels [57]. Unlike tamoxifen, raloxifene did not increase triglyceride concentrations in HepG2 human hepatocarcinoma cells in the absence or presence of oleic acid [32]. However, raloxifene prevented triglyceride accumulation in rat INS-1 insulin-producing cells under lipogenic conditions [58]. Thus, the effect of raloxifene on preventing triglyceride accumulation seems to be tissue-specific. The effect of raloxifene on serum leptin concentration has been investigated in several studies. In ovariectomized rats, raloxifene treatment reversed estrogen deficiency-induced hyperleptinemia and reduced total fat mass [45]. In two clinical studies conducted in postmenopausal women, raloxifene treatment (lasting for 3 and 6 months, respectively) significantly increased serum leptin level compared to baseline [59,60]. In contrast, another study found that serum leptin levels remained unchanged compared to baseline in postmenopausal women receiving raloxifene treatment, although serum leptin levels were significantly lower in postmenopausal women receiving raloxifene compared to those receiving no treatment [61]. Raloxifene treatment also maintained serum leptin at basal level and did not alter the body mass index (BMI) in women undergoing oophorectomy, whereas a significant increase in serum leptin levels was observed in the control group [62].

4. The effects of bazedoxifene and tissue-selective estrogen complex (TSEC) on metabolism Bazedoxifene (BZA) is a new SERM that exhibits estrogen antagonistic activity in breast and uterus and estrogen agonistic activity in bone, thus preventing osteoporosis while protecting the breast and uterus from estrogenic stimulation [63]. A new therapeutic strategy for menopausal symptoms involves the use of tissue selective estrogen complexes (TSECs) combining conjugated estrogens (CE) with bazedoxifene in a single tablet. The major innovation of TSEC is to provide all the benefits of CE treatment and protection of breast and uterus without using progestin [63,64]. As CE/BZA is a still novel therapy in postmenopausal women, how the combination will affect metabolism remains to be evaluated (Table 3). Initial studies showed CE/BZA regimen was associated with favorable effects on the lipid profile and minimal changes in coagulation [65,66], including reducing LDL cholesterol and total cholesterol level and increasing HDL cholesterol level. The impact of CE/BZA on metabolic parameters has been studied in ovariectomized (OVX) female mice. In OVX mice, CE/BZA and even BZA alone significantly attenuated OVX-induced body weight increase [67e69], and the accumulation of subcutaneous and visceral fat [67,68] without modifying lean body mass level [68].

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Table 2 Impacts of raloxifene on metabolism.

Raloxifene

Results

Study subjects Ovariectomized rat Postmenopausal women

Fasting blood glucose

Inhibited weight gain caused by estrogen deficiency [44,45] Prevented body weight gain and abdominal adiposity; fat distribution pattern shifted from android fat distribution to gynoid fat distribution [46] No effect on body weight, but increased fat-free mass and total body water [47] No effect on exercise-induced weight loss and fat-mass loss [48] Unchanged after 3-month, 6-month [49e52] or 12- month treatment [53]

Fasting insulin level

Unchanged after 3-month or 6-month treatment [49,50,52]

Glucose tolerance

No effect after 3-month, 6-month [49,50] or 12- month treatment [53]

Insulin sensitivity

Unchanged after 3-month or 6-month treatment [50e52], but in a subgroup of subjects with hyperinsulinemia, plasma insulin were significantly reduced [49] Decreased insulin sensitivity after 12-month treatment [53] Downregulated LDL cholesterol level [50,51,53,55] Unchanged HDL cholesterol level [50,51] Unchanged triglyceride level [32,50,51,56,57]

Body weight and fat mass

Lipid profile

Leptin level

Prevented triglyceride accumulation under lipogenic conditions Reversed estrogen deficiency-induced hyperleptinemia [45] Increased serum leptin level compared to the basal level [59,60] Unchanged serum leptin levels compared to the basal level, although the value was significantly lower compared to the subjects receiving no treatment [61] Serum leptin level were maintained as low as basal level [62]

Additionally, the combination of CE/BZA improved hepatic lipid homeostasis in OVX mice by decreasing hepatic triglyceride accumulation [67,68]. The reduction of hepatic steatosis following CE/ BZA treatment was the result of a suppressed de novo fatty acid synthesis, which was secondary to a decreased fatty acid synthase (FAS) expression and enzyme activity [67]. As a result, hepatic free fatty acid accumulation was repressed in OVX mice treated with CE/ BZA [70]. The combination CE/BZA also boosted lipid oxidation in liver through multiple critical pathways involved in lipid metabolism [67]. First, CE/BZA enhanced hepatic production and action of fibroblast growth factor-21 (FGF21), which plays an important role in stimulating hepatic lipid oxidation [71]. Second, CE/BZA stimulated hepatic expression of sirtuin1 (SIRT1) and its downstream target peroxisome proliferator-activated receptor a (PPARa), which are both critical transcriptional regulators of hepatic fatty acid

Postmenopausal women Postmenopausal women Postmenopausal women without [49 e51,53] or with T2D [52] Postmenopausal women without [49,50] or with T2D [52] Postmenopausal women without T2D [49,50,53] Postmenopausal women without [49e51] or with T2D [52] Postmenopausal women without T2D postmenopausal women Postmenopausal women Postmenopausal women [50,51,56,57] HepG2 cells [32] INS-1 cells [58] Ovariectomized rats Postmenopausal women Postmenopausal women Postmenopausal women undergoing oophorectomy surgery

oxidation. In addition, CE/BZA stimulated the phosphorylation of AMP-activated protein kinase a (AMPKa), the lipid metabolic master switch in the liver. Interestingly, CE/BZA also restored the physiological oscillatory activity of liver ERa that was diminished due to ovariectomy and prevented the effect of estrogen deficiency on hepatic steatosis [70]. Finally, treatment with CE/BZA increased ER transcriptional activity selectively in the arcuate nucleus of the hypothalamus, a key area for the control of energy homeostasis, suggesting that some of CE/BZA actions may be centrally mediated [69]. BZA/CE also improved glucose and insulin homeostasis in OVX mice. Blood glucose level was significantly decreased and insulin level was significantly increased after CE/BZA treatment under both fasting [67,68] and fed conditions [67], yet fasting blood glucose and insulin level were not significantly changed in postmenopausal women taking CE/BZA [65]. Moreover, CE/BZA-treated OVX mice

Table 3 Impacts of TSEC on metabolism.

TSEC (BZA/CE)

Body weight and fat mass

Steatosis

Lipid profile

Fasting blood glucose Fed blood glucose Fasting insulin Fed insulin Glucose tolerance Insulin sensitivity

Results

Study subjects

Attenuated body weight increase [67e69] Attenuated adipose tissue accumulation (both subcutaneous fat and visceral fat) [67,68] but no impact on lean body mass [68] Decreased triglyceride [67,68] or free fatty acid [70] accumulation

Ovariectomized C57BL/6 mice [67,68] or C57BL/6 heterozygous repTOPTMERE-Luc mice [69]

Increased lipid oxidation in the liver, achieved by affecting the expression of lipid oxidation regulators (FGF21, SIRT1 and PPARa) and the phosphorylation of AMPKa [67] Decreased LDL cholesterol level and total cholesterol level [65,66] Increased HDL cholesterol level [65,66] Increased triglyceride level [65,66] Decreased [67,68] No significant change [65] Decreased [67] Increased [67,68] No significant change [65] Increased [67] Improved [67,68] Improved [67,68]

Ovariectomized C57BL/6 mice [67,68] or C57BL/6 ERE-Luc mice [70] Ovariectomized C57BL/6 mice

Postmenopausal women Postmenopausal women Postmenopausal women Ovariectomized C57BL/6 mice Postmenopausal women Ovariectomized C57BL/6 mice Postmenopausal women Ovariectomized C57BL/6 mice

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exhibited enhanced glucose tolerance and insulin sensitivity [67,68]. 5. Conclusions Considering the dramatic rise in obesity and metabolic syndrome over the past decade, important clinical questions have emerged. Chief among these is how we can enhance the metabolic actions of estrogen in chronic therapies aiming at the prevention of metabolic dysfunction in postmenopausal women. Obviously, one solution is to target only the ER involved in energy balance, using novel SERMs that will retain the beneficial metabolic effects of estrogen on desired tissues while antagonizing ERs in breast and uterus. The advantage of using SERMs to prevent postmenopausal metabolic dysfunction is based on in-depth knowledge of estrogen and SERM efficacy and toxicity accumulated from decades of studies in preclinical models and in humans. Estrogen promotes metabolic homeostasis by way of at least three ERs acting on multiple tissues [72]. The challenge with estrogen, however, is its narrow therapeutic index when administered as a chronic treatment. Ten years after the WHI inappropriately concluded that the risks of hormone therapy outweighed its benefits and overstated the risks of breast cancer, coronary heart disease, stroke, and pulmonary embolism with estrogen-progestin treatment, a global consensus statement endorsed by most menopausal societies states that hormone therapy plays a beneficial role in short-term treatment of menopausal symptoms [73]. Thus, at least during this interval, the metabolic dysfunction caused by estrogen deficiency can be addressed. Interestingly, a novel SERM (GSK232802A) reduced body weight and adiposity in ovariectomized nonhuman primates by suppressing food intake and increasing activity, particularly in the most sedentary individuals [74]. These findings in primates suggest that SERM treatment may also counteract weight gain in postmenopausal women. The inherent beauty of using TSECs combining estrogen with a SERM is that it retains the beneficial effects of estrogen to prevent metabolic dysfunction and other chronic degenerative diseases, while at the same time blocking ERs in breast and uterus without using progestin. Studies are ongoing to address the effect of TSECs combining CE and BZA to prevent metabolic dysfunction in obese postmenopausal women [75,76]. Disclosure FMJ received research funding from Pfizer, Inc. Other authors declare no competing financial interest. Acknowledgments We apologize to those investigators and studies we were unable to cite in this Review because of space limitation. We thank Loula Burton at Tulane University Health Sciences Center for editorial assistance. This work was supported by grants from the National Institutes of Health (DK074970, HD044405), the American Diabetes Association (7-13-BS-101) and an investigator initiated grant from Pfizer, Inc to F.M.J. References [1] M.W. Pfaffl, et al., Tissue-specific expression pattern of estrogen receptors (ER): quantification of ER alpha and ER beta mRNA with real-time RT-PCR, APMIS 109 (5) (2001) 345e355. [2] M.K. Tee, et al., Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta, Mol. Biol. Cell 15 (3) (2004) 1262e1272.

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Please cite this article in press as: B. Xu, et al., Effect of selective estrogen receptor modulators on metabolic homeostasis, Biochimie (2015), http://dx.doi.org/10.1016/j.biochi.2015.06.018