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 article info Article history: Received 19 April 2015 Accepted 24 June 2015 Available online xxx Keywords: Selective estrogen receptor modulators Tissue-selective estrogen complex Bazedoxifene Metabolic syndrome Energy metabolism Diabetes abstract 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 post- menopausal osteoporosis respectively. The third-generation SERM, bazedoxifene (BZA), effectively pre- vents 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. 1. Introduction Following the increase in longevity in developed countries, most women will spend the second half of their lives in a state of es- trogen deficiency. In addition to predisposing to cardiovascular, skeletal and neurodegenerative diseases, estrogen deficiency en- hances metabolic dysfunction predisposing to obesity, metabolic syndrome and type 2 diabetes (T2D). Thus the contribution of es- trogen 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 meta- bolic homeostasis while also avoiding its side effects on repro- ductive tissues. Selective estrogen receptor modulators (SERMs) are a class of compounds that interact with estrogen receptors (ERs) as ER li- gands 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 distri- bution 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. Ral- oxifene, which retains anti-estrogenic activity in breast tissue [9] and exhibits estrogenic activity in bone, can also prevent osteo- porosis [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 con- jugated 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 Abbreviations: SERMs, selective estrogen receptor modulators; ER, estrogen receptor; BZA, bazedoxifene; CE, conjugated estrogens; TSEC, tissue-selective es- trogen 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 differentiation- associated 2; Lcn13, lipocalin 13; PPARg, peroxisome proliferator-activated recep- tor 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 Uni- versity Health Sciences Center,1430 Tulane Ave SL-53, New Orleans, LA 70112, USA. E-mail address: fmauvais@tulane.edu (F. Mauvais-Jarvis). Contents lists available at ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi http://dx.doi.org/10.1016/j.biochi.2015.06.018 0300-9084/© 2015 Published by Elsevier B.V. Biochimie xxx (2015) 1e6 Please cite this article inpress 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