Nuclear and Membrane Actions of Estrogen Receptor Alpha: Contribution to the Regulation of Energy and Glucose Homeostasis

  • Maeva Guillaume
  • Alexandra Montagner
  • Coralie Fontaine
  • Françoise Lenfant
  • Jean-François Arnal
  • Pierre Gourdy
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)


Estrogen receptor alpha (ERα) has been demonstrated to play a key role in reproduction but also to exert numerous functions in nonreproductive tissues. Accordingly, ERα is now recognized as a key regulator of energy homeostasis and glucose metabolism and mediates the protective effects of estrogens against obesity and type 2 diabetes. This chapter attempts to summarize our current understanding of the mechanisms of ERα activation and their involvement in the modulation of energy balance and glucose metabolism. We first focus on the experimental studies that constitute the basis of the understanding of ERα as a nuclear receptor and more specifically on the key roles played by its two activation functions (AFs). We depict the consequences of the selective inactivation of these AFs in mouse models, which further underline the prominent role of nuclear ERα in the prevention of obesity and diabetes, as on the reproductive tract and the vascular system. Besides these nuclear actions, a fraction of ERα is associated with the plasma membrane and activates nonnuclear signaling from this site. Such rapid effects, called membrane-initiated steroid signals (MISS), have been characterized in a variety of cell lines and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS as well as the generation of mice expressing an ERα protein impeded for membrane localization has just begun to unravel the physiological role of MISS in vivo and their contribution to ERα-mediated metabolic protection. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators.



The authors thank Raphael Metivier and Gilles Flouriot (Rennes, France), Pierre Chambon (Strasbourg, France), and John and Benita Katzenellenbogen (Urbana, USA) for long-term collaboration and fruitful discussions.


  1. Acconcia, F., Ascenzi, P., Bocedi, A., Spisni, E., Tomasi, V., Trentalance, A., Visca, p., & Marino, M. (2005). Palmitoylation-dependent estrogen receptor alpha membrane localization: Regulation by 17beta-estradiol. Molecular Biology of the Cell, 16, 231–237.PubMedCentralCrossRefPubMedGoogle Scholar
  2. Adlanmerini, M., Solinhac, R., Abot, A., Fabre, A., Raymond-Letron, I., Guihot, A. L., Boudou, F., Sautier, L., Vessieres, E., Kim, S. H., Liere, P., Fontaine, C., Krust, A., Chambon, P., Katzenellenbogen, J. A., Gourdy, P., Shaul, P. W., Henrion, D., Arnal, J. F., & Lenfant, F. (2014). Mutation of the palmitoylation site of estrogen receptor alpha in vivo reveals tissue-specific roles for membrane versus nuclear actions. Proceedings of the National Academy of Sciences of the United States of America, 111, E283–E290.CrossRefPubMedGoogle Scholar
  3. Ahlbory-Dieker, D. L., Stride, B. D., Leder, G., Schkoldow, J., Trolenberg, S., Seidel, H., Otto, C., Sommer, A., Parker, M. G., Schutz, G., & Wintermantel, T. M. (2009). DNA binding by estrogen receptor-alpha is essential for the transcriptional response to estrogen in the liver and the uterus. Molecular Endocrinology, 23, 1544–1555.PubMedCentralCrossRefPubMedGoogle Scholar
  4. Ali, S., Metzger, D., Bornert, J. M., & Chambon, P. (1993). Modulation of transcriptional activation by ligand-dependent phosphorylation of the human oestrogen receptor A/B region. The EMBO Journal, 12, 1153–1160.PubMedCentralPubMedGoogle Scholar
  5. Arao, Y., Hamilton, K. J., Ray, M. K., Scott, G., Mishina, Y., & Korach, K. S. (2011). Estrogen receptor alpha AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators. Proceedings of the National Academy of Sciences of the United States of America, 108, 14986–14991.PubMedCentralCrossRefPubMedGoogle Scholar
  6. Arnal, J. F., Fontaine, C., Billon-gales, A., Favre, J., Laurell, H., Lenfant, F., & Gourdy, P. (2010). Estrogen receptors and endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 1506–1512.CrossRefPubMedGoogle Scholar
  7. Arnal, J. F., Lenfant, F., Metivier, R., Flouriot, G., Henrion, D., Adlanmerini, M., Fontaine, C., Gourdy, P., Chambon, P., Katzenellenbogen, B., & Katzenellenbogen, J. (2017). Membrane and nuclear estrogen receptor alpha actions: From tissue specificity to medical implications. Physiological Reviews, 97, 1045–1087.CrossRefPubMedGoogle Scholar
  8. Ascenzi, P., Bocedi, A., & Marino, M. (2006). Structure-function relationship of estrogen receptor alpha and beta: Impact on human health. Molecular Aspects of Medicine, 27, 299–402.CrossRefPubMedGoogle Scholar
  9. Billon-Gales, A., Fontaine, C., Douin-Echinard, V., Delpy, L., Berges, H., Calippe, B., Lenfant, F., Laurell, H., Guery, J. C., Gourdy, P., & Arnal, J. F. (2009a). Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice. Circulation, 120, 2567–2576.CrossRefPubMedGoogle Scholar
  10. Billon-gales, A., Fontaine, C., Filipe, C., Douin-Echinard, V., Fouque, M. J., Flouriot, G., Gourdy, P., Lenfant, F., Laurell, H., Krust, A., Chambon, P., & Arnal, J. F. (2009b). The transactivating function 1 of estrogen receptor {alpha} is dispensable for the vasculoprotective actions of 17{beta}-estradiol. Proceedings of the National Academy of Sciences of the United States of America, 106, 2053–2058.PubMedCentralCrossRefPubMedGoogle Scholar
  11. Billon-Gales, A., Krust, A., Fontaine, C., Abot, A., Flouriot, G., Toutain, C., Berges, H., Gadeau, A. P., Lenfant, F., Gourdy, P., Chambon, P., & Arnal, J. F. (2011). Activation function 2 (AF2) of estrogen receptor-{alpha} is required for the atheroprotective action of estradiol but not to accelerate endothelial healing. Proceedings of the National Academy of Sciences of the United States of America, 108, 13311–13316.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Bolego, C., Cignarella, A., Sanvito, P., Pelosi, V., Pellegatta, F., Puglisi, L., & Pinna, C. (2005). The acute estrogenic dilation of rat aorta is mediated solely by selective estrogen receptor-alpha agonists and is abolished by estrogen deprivation. The Journal of Pharmacology and Experimental Therapeutics, 313, 1203–1208.CrossRefPubMedGoogle Scholar
  13. Bonds, D. E., Lasser, N., Qi, L., Brzyski, R., Caan, B., Heiss, G., Limacher, M. C., Liu, J. H., Mason, E., Oberman, A., O’sullivan, M. J., Phillips, L. S., Prineas, R. J., & Tinker, L. (2006). The effect of conjugated equine oestrogen on diabetes incidence: The women’s health initiative randomised trial. Diabetologia, 49, 459–468.CrossRefPubMedGoogle Scholar
  14. Borjesson, A. E., Windahl, S. H., Lagerquist, M. K., Engdahl, C., Frenkel, B., Moverare-Skrtic, S., Sjogren, K., Kindblom, J. M., Stubelius, A., Islander, U., Antal, M. C., Krust, A., Chambon, P., & Ohlsson, C. (2011). Roles of transactivating functions 1 and 2 of estrogen receptor-{alpha} in bone. Proceedings of the National Academy of Sciences of the United States of America, 108, 6288–6293.PubMedCentralCrossRefPubMedGoogle Scholar
  15. Brouchet, L., Krust, A., Dupont, S., Chambon, P., Bayard, F., & Arnal, J. F. (2001). Estradiol accelerates reendothelialization in mouse carotid artery through estrogen receptor-alpha but not estrogen receptor-beta. Circulation, 103, 423–428.CrossRefPubMedGoogle Scholar
  16. Brzozowski, A. M., Pike, A. C., Dauter, Z., Hubbard, R. E., Bonn, T., Engstrom, O., Ohman, L., Greene, G. L., Gustafsson, J. A., & Carlquist, M. (1997). Molecular basis of agonism and antagonism in the oestrogen receptor. Nature, 389, 753–758.CrossRefPubMedGoogle Scholar
  17. Bunone, G., Briand, P. A., Miksicek, R. J., & Picard, D. (1996). Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. The EMBO Journal, 15, 2174–2183.PubMedCentralPubMedGoogle Scholar
  18. Carson-Jurica, M. A., Schrader, W. T., & O’malley, B. W. (1990). Steroid receptor family: Structure and functions. Endocrine Reviews, 11, 201–220.CrossRefPubMedGoogle Scholar
  19. Caulin-Glaser, T., Garcia-Cardena, G., Sarrel, P., Sessa, W. C., & Bender, J. R. (1997). 17 beta-estradiol regulation of human endothelial cell basal nitric oxide release, independent of cytosolic Ca2+ mobilization. Circulation Research, 81, 885–892.CrossRefPubMedGoogle Scholar
  20. Chambliss, K. L., Yuhanna, I. S., Anderson, R. G., Mendelsohn, M. E., & Shaul, P. W. (2002). ERbeta has nongenomic action in caveolae. Molecular Endocrinology, 16, 938–946.PubMedGoogle Scholar
  21. Chambliss, K. L., Wu, Q., Oltmann, S., Konaniah, E. S., Umetani, M., Korach, K. S., Thomas, G. D., Mineo, C., Yuhanna, I. S., Kim, S. H., Madak-Erdogan, Z., Maggi, A., Dineen, S. P., Roland, C. L., Hui, D. Y., Brekken, R. A., Katzenellenbogen, J. A., Katzenellenbogen, B. S., & Shaul, P. W. (2010). Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. The Journal of Clinical Investigation, 120, 2319–2330.PubMedCentralCrossRefPubMedGoogle Scholar
  22. Chambliss, K. L., Barrera, J., Umetani, M., Umetani, J., Kim, S. H., Madak-Erdogan, Z., Huang, L., Katzenellenbogen, B. S., Katzenellenbogen, J. A., Mineo, C., & Shaul, P. W. (2016). Nonnuclear estrogen receptor activation improves hepatic steatosis in female mice. Endocrinology, 157, 3731–3741.PubMedCentralCrossRefPubMedGoogle Scholar
  23. Chantalat, E., Boudou, F., Laurell, H., Palierne, G., Houtman, R., Melchers, D., Rochaix, P., Filleron, T., Stella, A., Burlet-Schiltz, O., Brouchet, A., Flouriot, G., Metivier, R., Arnal, J. F., Fontaine, C., & Lenfant, F. (2016). The AF-1-deficient estrogen receptor ERalpha46 isoform is frequently expressed in human breast tumors. Breast Cancer Research, 18, 123.PubMedCentralCrossRefPubMedGoogle Scholar
  24. Chen, Z., Yuhanna, I. S., Galcheva-Gargova, Z., Karas, R. H., Mendelsohn, M. E., & Shaul, P. W. (1999). Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. The Journal of Clinical Investigation, 103, 401–406.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Chen, D. B., Bird, I. M., Zheng, J., & Magness, R. R. (2004). Membrane estrogen receptor-dependent extracellular signal-regulated kinase pathway mediates acute activation of endothelial nitric oxide synthase by estrogen in uterine artery endothelial cells. Endocrinology, 145, 113–125.CrossRefPubMedGoogle Scholar
  26. Cooke, P. S., Heine, P. A., Taylor, J. A., & Lubahn, D. B. (2001). The role of estrogen and estrogen receptor-alpha in male adipose tissue. Molecular and Cellular Endocrinology, 178, 147–154.CrossRefPubMedGoogle Scholar
  27. Dan, P., Cheung, J. C., Scriven, D. R., & Moore, E. D. (2003). Epitope-dependent localization of estrogen receptor-alpha, but not -beta, in en face arterial endothelium. American Journal of Physiology. Heart and Circulatory Physiology, 284, H1295–H1306.CrossRefPubMedGoogle Scholar
  28. Danielian, P. S., White, R., Lees, J. A., & Parker, M. G. (1992). Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors. The EMBO Journal, 11, 1025–1033.PubMedCentralPubMedGoogle Scholar
  29. Darblade, B., Pendaries, C., Krust, A., Dupont, S., Fouque, M. J., Rami, J., Chambon, P., Bayard, F., & Arnal, J. F. (2002). Estradiol alters nitric oxide production in the mouse aorta through the alpha-, but not beta-, estrogen receptor. Circulation Research, 90, 413–419.CrossRefPubMedGoogle Scholar
  30. Davis, K. E., Carstens, E. J., Irani, B. G., Gent, L. M., Hahner, L. M., & Clegg, D. J. (2014). Sexually dimorphic role of G protein-coupled estrogen receptor (GPER) in modulating energy homeostasis. Hormones and Behavior, 66, 196–207.PubMedCentralCrossRefPubMedGoogle Scholar
  31. Dupont, S., Krust, A., Gansmuller, A., Dierich, A., Chambon, P., & Mark, M. (2000). Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development, 127, 4277–4291.PubMedGoogle Scholar
  32. Filardo, E. J., Quinn, J. A., Bland, K. I., & Frackelton, A. R., Jr. (2000). Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Molecular Endocrinology, 14, 1649–1660.CrossRefPubMedGoogle Scholar
  33. Foulds, C. E., Feng, Q., Ding, C., Bailey, S., Hunsaker, T. L., Malovannaya, A., Hamilton, R. A., Gates, L. A., Zhang, Z., Li, C., Chan, D., Bajaj, A., Callaway, C. G., Edwards, D. P., Lonard, D. M., Tsai, S. Y., Tsai, M. J., Qin, J., & O’Malley, B. W. (2013). Proteomic analysis of coregulators bound to ERalpha on DNA and nucleosomes reveals coregulator dynamics. Molecular Cell, 51, 185–199.PubMedCentralCrossRefPubMedGoogle Scholar
  34. Garcia-Cardena, G., Oh, P., Liu, J., Schnitzer, J. E., & Sessa, W. C. (1996). Targeting of nitric oxide synthase to endothelial cell caveolae via palmitoylation: Implications for nitric oxide signaling. Proceedings of the National Academy of Sciences of the United States of America, 93, 6448–6453.PubMedCentralCrossRefPubMedGoogle Scholar
  35. Green, S., & Chambon, P. (1987). Oestradiol induction of a glucocorticoid-responsive gene by a chimaeric receptor. Nature, 325, 75–78.CrossRefPubMedGoogle Scholar
  36. Green, S., Walter, P., Kumar, V., Krust, A., Bornert, J. M., Argos, P., & Chambon, P. (1986). Human oestrogen receptor cDNA: Sequence, expression and homology to v-erb-A. Nature, 320, 134–139.CrossRefPubMedGoogle Scholar
  37. Grumbach, M. M., & Auchus, R. J. (1999). Estrogen: Consequences and implications of human mutations in synthesis and action. The Journal of Clinical Endocrinology and Metabolism, 84, 4677–4694.PubMedGoogle Scholar
  38. Guillaume, M., Handgraaf, S., Fabre, A., Raymond-Letron, I., Riant, E., Montagner, A., Vinel, A., Buscato, M., Smirnova, N., Fontaine, C., Guillou, H., Arnal, J. F., & Gourdy, P. (2017). Selective activation of estrogen receptor alpha activation function-1 is sufficient to prevent obesity, steatosis, and insulin resistance in mouse. The American Journal of Pathology, 187, 1273–1287.CrossRefPubMedGoogle Scholar
  39. Hafezi-Moghadam, A., Simoncini, T., Yang, Z., Limbourg, F. P., Plumier, J. C., Rebsamen, M. C., Hsieh, C. M., Chui, D. S., Thomas, K. L., Prorock, A. J., Laubach, V. E., Moskowitz, M. A., French, B. A., Ley, K., & Liao, J. K. (2002). Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nature Medicine, 8, 473–479.PubMedCentralCrossRefPubMedGoogle Scholar
  40. Hammes, S. R., & Levin, E. R. (2007). Extranuclear steroid receptors: Nature and actions. Endocrine Reviews, 28, 726–741.CrossRefPubMedGoogle Scholar
  41. Handgraaf, S., Riant, E., Fabre, A., Waget, A., Burcelin, R., Liere, P., Krust, A., Chambon, P., Arnal, J. F., & Gourdy, P. (2013). Prevention of obesity and insulin resistance by estrogens requires ERalpha activation function-2 (ERalphaAF-2), whereas ERalphaAF-1 is dispensable. Diabetes, 62, 4098–4108.PubMedCentralCrossRefPubMedGoogle Scholar
  42. Harrington, W. R., Kim, S. H., Funk, C. C., Madak-Erdogan, Z., Schiff, R., Katzenellenbogen, J. A., & Katzenellenbogen, B. S. (2006). Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action. Molecular Endocrinology, 20, 491–502.CrossRefPubMedGoogle Scholar
  43. Heine, P. A., Taylor, J. A., Iwamoto, G. A., Lubahn, D. B., & Cooke, P. S. (2000). Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proceedings of the National Academy of Sciences of the United States of America, 97, 12729–12734.PubMedCentralCrossRefPubMedGoogle Scholar
  44. Heldring, N., Pike, A., Andersson, S., Matthews, J., Cheng, G., Hartman, J., Tujague, M., Strom, A., Treuter, E., Warner, M., & Gustafsson, J. A. (2007). Estrogen receptors: How do they signal and what are their targets. Physiological Reviews, 87, 905–931.CrossRefPubMedGoogle Scholar
  45. Hewitt, S. C., Li, L., Grimm, S. A., Winuthayanon, W., Hamilton, K. J., Pockette, B., Rubel, C. A., Pedersen, L. C., Fargo, D., Lanz, R. B., Demayo, F. J., Schutz, G., & Korach, K. S. (2014). Novel DNA motif binding activity observed in vivo with an estrogen receptor alpha mutant mouse. Molecular Endocrinology, 28, 899–911.PubMedCentralCrossRefPubMedGoogle Scholar
  46. Horwitz, K. B., Jackson, T. A., Bain, D. L., Richer, J. K., Takimoto, G. S., & Tung, L. (1996). Nuclear receptor coactivators and corepressors. Molecular Endocrinology, 10, 1167–1177.PubMedGoogle Scholar
  47. Iafrati, M. D., Karas, R. H., Ronovitz, M., Kim, S., Sullivan, T. R., Jr., Lubahn, D. B., O’donnell, T. F., Jr., Korach, K. S., & Mendelsohn, M. E. (1997). Estrogen inhibits the vascular injury response in estrogen receptor alpha-deficient mice. Nature Medicine, 3, 545–548.CrossRefPubMedGoogle Scholar
  48. Jakacka, M., Ito, M., Martinson, F., Ishikawa, T., Lee, E. J., & Jameson, J. L. (2002). An estrogen receptor (ER)alpha deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Molecular Endocrinology, 16, 2188–2201.CrossRefPubMedGoogle Scholar
  49. Jensen, E. V., & Desombre, E. R. (1973). Estrogen-receptor interaction. Science, 182, 126–134.CrossRefPubMedGoogle Scholar
  50. Jones, M. E., Thorburn, A. W., Britt, K. L., Hewitt, K. N., Wreford, N. G., PROIETTO, J., Oz, O. K., Leury, B. J., Robertson, K. M., Yao, S., & Simpson, E. R. (2000). Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proceedings of the National Academy of Sciences of the United States of America, 97, 12735–12740.PubMedCentralCrossRefPubMedGoogle Scholar
  51. Kanaya, A. M., Herrington, D., Vittinghoff, E., Lin, F., Grady, D., Bittner, V., Cauley, J. A., & Barrett-Connor, E. (2003). Glycemic effects of postmenopausal hormone therapy: The heart and estrogen/progestin replacement study. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine, 138, 1–9.CrossRefPubMedGoogle Scholar
  52. Kato, S., Endoh, H., Masuhiro, Y., Kitamoto, T., Uchiyama, S., Sasaki, H., Masushige, S., Gotoh, Y., Nishida, E., Kawashima, H., Metzger, D., & Chambon, P. (1995). Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science, 270, 1491–1494.CrossRefPubMedGoogle Scholar
  53. Krust, A., Green, S., Argos, P., Kumar, V., Walter, P., Bornert, J. M., & Chambon, P. (1986). The chicken oestrogen receptor sequence: Homology with v-erbA and the human oestrogen and glucocorticoid receptors. The EMBO Journal, 5, 891–897.PubMedCentralPubMedGoogle Scholar
  54. Kukowska-Latallo, J. F., Candido, K. A., Cao, Z., Nigavekar, S. S., Majoros, I. J., Thomas, T. P., Balogh, L. P., Khan, M. K., & Baker, J. R., Jr. (2005). Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Research, 65, 5317–5324.CrossRefPubMedGoogle Scholar
  55. Kumar, R., & Thompson, E. B. (1999). The structure of the nuclear hormone receptors. Steroids, 64, 310–319.CrossRefPubMedGoogle Scholar
  56. Kumar, P., Wu, Q., Chambliss, K. L., Yuhanna, I. S., Mumby, S. M., Mineo, C., Tall, G. G., & Shaul, P. W. (2007). Direct interactions with G alpha i and G betagamma mediate nongenomic signaling by estrogen receptor alpha. Molecular Endocrinology, 21, 1370–1380.CrossRefPubMedGoogle Scholar
  57. Lange, C. A., Gioeli, D., Hammes, S. R., & Marker, P. C. (2007). Integration of rapid signaling events with steroid hormone receptor action in breast and prostate cancer. Annual Review of Physiology, 69, 171–199.CrossRefPubMedGoogle Scholar
  58. Langer, G., Bader, B., Meoli, L., Isensee, J., Delbeck, M., Noppinger, P. R., & Otto, C. (2010). A critical review of fundamental controversies in the field of GPR30 research. Steroids, 75, 603–610.CrossRefPubMedGoogle Scholar
  59. Lantin-Hermoso, R. L., Rosenfeld, C. R., Yuhanna, I. S., German, Z., Chen, Z., & Shaul, P. W. (1997). Estrogen acutely stimulates nitric oxide synthase activity in fetal pulmonary artery endothelium. The American Journal of Physiology, 273, L119–L126.PubMedGoogle Scholar
  60. Lavinsky, R. M., Jepsen, K., Heinzel, T., Torchia, J., Mullen, T. M., Schiff, R., Del-Rio, A. L., Ricote, M., Ngo, S., Gemsch, J., Hilsenbeck, S. G., Osborne, C. K., Glass, C. K., Rosenfeld, M. G., & Rose, D. W. (1998). Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. Proceedings of the National Academy of Sciences of the United States of America, 95, 2920–2925.PubMedCentralCrossRefPubMedGoogle Scholar
  61. Le May, C., Chu, K., Hu, M., Ortega, C. S., Simpson, E. R., Korach, K. S., Tsai, M. J., & Mauvais-Jarvis, F. (2006). Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proceedings of the National Academy of Sciences of the United States of America, 103, 9232–9237.PubMedCentralCrossRefPubMedGoogle Scholar
  62. Le Romancer, M., Treilleux, I., Leconte, N., Robin-Lespinasse, Y., Sentis, S., Bouchekioua-Bouzaghou, K., Goddard, S., Gobert-Gosse, S., & Corbo, L. (2008). Regulation of estrogen rapid signaling through arginine methylation by PRMT1. Molecular Cell, 31, 212–221.CrossRefPubMedGoogle Scholar
  63. Le Romancer, M., Poulard, C., Cohen, P., Sentis, S., Renoir, J. M., & Corbo, L. (2011). Cracking the estrogen receptor’s posttranslational code in breast tumors. Endocrine Reviews, 32, 597–622.CrossRefPubMedGoogle Scholar
  64. Lees, J. A., Fawell, S. E., & Parker, M. G. (1989). Identification of constitutive and steroid-dependent transactivation domains in the mouse oestrogen receptor. Journal of Steroid Biochemistry, 34, 33–39.CrossRefPubMedGoogle Scholar
  65. Leong, H., Sloan, J. R., Nash, P. D., & Greene, G. L. (2005). Recruitment of histone deacetylase 4 to the N-terminal region of estrogen receptor alpha. Molecular Endocrinology, 19, 2930–2942.CrossRefPubMedGoogle Scholar
  66. Levin, E. R. (2009). G protein-coupled receptor 30: Estrogen receptor or collaborator? Endocrinology, 150, 1563–1565.PubMedCentralCrossRefPubMedGoogle Scholar
  67. Levin, E. R., & Hammes, S. R. (2016). Nuclear receptors outside the nucleus: Extranuclear signalling by steroid receptors. Nature Reviews. Molecular Cell Biology, 17, 783–797.PubMedCentralCrossRefPubMedGoogle Scholar
  68. Levin, E. R., & Pietras, R. J. (2008). Estrogen receptors outside the nucleus in breast cancer. Breast Cancer Research and Treatment, 108, 351–361.CrossRefPubMedGoogle Scholar
  69. Li, L., Haynes, M. P., & Bender, J. R. (2003). Plasma membrane localization and function of the estrogen receptor alpha variant (ER46) in human endothelial cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 4807–4812.PubMedCentralCrossRefPubMedGoogle Scholar
  70. Liu, S., & Mauvais-Jarvis, F. (2010). Minireview: Estrogenic protection of beta-cell failure in metabolic diseases. Endocrinology, 151, 859–864.CrossRefPubMedGoogle Scholar
  71. Liu, Z., Merkurjev, D., Yang, F., Li, W., Oh, S., Friedman, M. J., Song, X., Zhang, F., Ma, Q., Ohgi, K. A., Krones, A., & Rosenfeld, M. G. (2014). Enhancer activation requires trans-recruitment of a mega transcription factor complex. Cell, 159, 358–373.PubMedCentralCrossRefPubMedGoogle Scholar
  72. Lonard, D. M., & O’malley, B. W. (2007). Nuclear receptor coregulators: Judges, juries, and executioners of cellular regulation. Molecular Cell, 27, 691–700.CrossRefPubMedGoogle Scholar
  73. Louet, J. F., Lemay, C., & Mauvais-Jarvis, F. (2004). Antidiabetic actions of estrogen: Insight from human and genetic mouse models. Current Atherosclerosis Reports, 6, 180–185.CrossRefPubMedGoogle Scholar
  74. Lubahn, D. B., Moyer, J. S., Golding, T. S., Couse, J. F., Korach, K. S., & Smithies, O. (1993). Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. Proceedings of the National Academy of Sciences of the United States of America, 90, 11162–11166.PubMedCentralCrossRefPubMedGoogle Scholar
  75. Madak-Erdogan, Z., Kim, S. H., Gong, P., Zhao, Y. C., Zhang, H., Chambliss, K. L., Carlson, K. E., Mayne, C. G., Shaul, P. W., Korach, K. S., Katzenellenbogen, J. A., & Katzenellenbogen, B. S. (2016). Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. Science Signaling, 9, ra53.PubMedCentralCrossRefPubMedGoogle Scholar
  76. Mader, S., Kumar, V., De Verneuil, H., & Chambon, P. (1989). Three amino acids of the oestrogen receptor are essential to its ability to distinguish an oestrogen from a glucocorticoid-responsive element. Nature, 338, 271–274.CrossRefPubMedGoogle Scholar
  77. Mangelsdorf, D. J., & Evans, R. M. (1995). The RXR heterodimers and orphan receptors. Cell, 83, 841–850.CrossRefPubMedGoogle Scholar
  78. Margolis, K. L., Bonds, D. E., Rodabough, R. J., Tinker, L., Phillips, L. S., Allen, C., Bassford, T., Burke, G., Torrens, J., & Howard, B. V. (2004). Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: Results from the Women's Health Initiative Hormone Trial. Diabetologia, 47, 1175–1187.CrossRefPubMedGoogle Scholar
  79. Marino, M., & Ascenzi, P. (2008). Membrane association of estrogen receptor alpha and beta influences 17beta-estradiol-mediated cancer cell proliferation. Steroids, 73, 853–858.CrossRefPubMedGoogle Scholar
  80. Mauvais-Jarvis, F. (2016). Role of sex steroids in beta cell function, growth, and survival. Trends in Endocrinology and Metabolism, 27, 844–855.PubMedCentralCrossRefPubMedGoogle Scholar
  81. Mauvais-Jarvis, F., Manson, J. E., Stevenson, J. C., & Fonseca, V. A. (2017). Menopausal hormone therapy and type 2 diabetes prevention: Evidence, mechanisms, and clinical implications. Endocrine Reviews, 38, 173–188.CrossRefPubMedGoogle Scholar
  82. Mcdevitt, M. A., Glidewell-Kenney, C., Jimenez, M. A., Ahearn, P. C., Weiss, J., Jameson, J. L., & Levine, J. E. (2008). New insights into the classical and non-classical actions of estrogen: Evidence from estrogen receptor knock-out and knock-in mice. Molecular and Cellular Endocrinology, 290, 24–30.PubMedCentralCrossRefPubMedGoogle Scholar
  83. Mckenna, N. J., & O’malley, B. W. (2002). Combinatorial control of gene expression by nuclear receptors and coregulators. Cell, 108, 465–474.CrossRefPubMedGoogle Scholar
  84. Mendelsohn, M. E., & Karas, R. H. (2010). Rapid progress for non-nuclear estrogen receptor signaling. The Journal of Clinical Investigation, 120, 2277–2279.PubMedCentralCrossRefPubMedGoogle Scholar
  85. Metivier, R., Stark, A., Flouriot, G., Hubner, M. R., Brand, H., Penot, G., Manu, D., Denger, S., Reid, G., Kos, M., Russell, R. B., Kah, O., Pakdel, F., & Gannon, F. (2002). A dynamic structural model for estrogen receptor-alpha activation by ligands, emphasizing the role of interactions between distant A and E domains. Molecular Cell, 10, 1019–1032.CrossRefPubMedGoogle Scholar
  86. Metivier, R., Penot, G., Carmouche, R. P., Hubner, M. R., Reid, G., Denger, S., Manu, D., Brand, H., Kos, M., Benes, V., & Gannon, F. (2004). Transcriptional complexes engaged by apo-estrogen receptor-alpha isoforms have divergent outcomes. The EMBO Journal, 23, 3653–3666.PubMedCentralCrossRefPubMedGoogle Scholar
  87. Metzger, D., Ali, S., Bornert, J. M., & Chambon, P. (1995). Characterization of the amino-terminal transcriptional activation function of the human estrogen receptor in animal and yeast cells. The Journal of Biological Chemistry, 270, 9535–9542.CrossRefPubMedGoogle Scholar
  88. Meyer, M. R., Prossnitz, E. R., & Barton, M. (2011). The G protein-coupled estrogen receptor GPER/GPR30 as a regulator of cardiovascular function. Vascular Pharmacology, 55, 17–25.PubMedCentralCrossRefPubMedGoogle Scholar
  89. Moras, D., & Gronemeyer, H. (1998). The nuclear receptor ligand-binding domain: Structure and function. Current Opinion in Cell Biology, 10, 384–391.CrossRefPubMedGoogle Scholar
  90. Morishima, A., Grumbach, M. M., Simpson, E. R., Fisher, C., & Qin, K. (1995). Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. The Journal of Clinical Endocrinology and Metabolism, 80, 3689–3698.PubMedGoogle Scholar
  91. Mosselman, S., Polman, J., & Dijkema, R. (1996). ER beta: Identification and characterization of a novel human estrogen receptor. FEBS Letters, 392, 49–53.CrossRefPubMedGoogle Scholar
  92. Nadal, A., Alonso-Magdalena, P., Soriano, S., Quesada, I., & Ropero, A. B. (2009). The pancreatic beta-cell as a target of estrogens and xenoestrogens: Implications for blood glucose homeostasis and diabetes. Molecular and Cellular Endocrinology, 304, 63–68.CrossRefPubMedGoogle Scholar
  93. O’brien, J. E., Peterson, T. J., Tong, M. H., Lee, E. J., Pfaff, L. E., Hewitt, S. C., Korach, K. S., Weiss, J., & Jameson, J. L. (2006). Estrogen-induced proliferation of uterine epithelial cells is independent of estrogen receptor alpha binding to classical estrogen response elements. The Journal of Biological Chemistry, 281, 26683–26692.CrossRefPubMedGoogle Scholar
  94. Palierne, G., Fabre, A., Solinhac, R., Le Peron, C., Avner, S., Lenfant, F., Fontaine, C., Salbert, G., Flouriot, G., Arnal, J. F., & Metivier, R. (2016). Changes in gene expression and estrogen receptor cistrome in mouse liver upon acute E2 treatment. Molecular Endocrinology, 30, 709–732.PubMedCentralCrossRefPubMedGoogle Scholar
  95. Pare, G., Krust, A., Karas, R. H., Dupont, S., Aronovitz, M., Chambon, P., & Mendelsohn, M. E. (2002). Estrogen receptor-alpha mediates the protective effects of estrogen against vascular injury. Circulation Research, 90, 1087–1092.CrossRefPubMedGoogle Scholar
  96. Park, C. J., Zhao, Z., Glidewell-Kenney, C., Lazic, M., Chambon, P., Krust, A., Weiss, J., Clegg, D. J., Dunaif, A., Jameson, J. L., & Levine, J. E. (2011). Genetic rescue of nonclassical ERalpha signaling normalizes energy balance in obese Eralpha-null mutant mice. The Journal of Clinical Investigation, 121, 604–612.PubMedCentralCrossRefPubMedGoogle Scholar
  97. Pedram, A., Razandi, M., Sainson, R. C., Kim, J. K., Hughes, C. C., & Levin, E. R. (2007). A conserved mechanism for steroid receptor translocation to the plasma membrane. The Journal of Biological Chemistry, 282, 22278–22288.CrossRefPubMedGoogle Scholar
  98. Pedram, A., Razandi, M., Kim, J. K., O’mahony, F., Lee, E. Y., Luderer, U., & Levin, E. R. (2009). Developmental phenotype of a membrane only estrogen receptor alpha (MOER) mouse. The Journal of Biological Chemistry, 284, 3488–3495.PubMedCentralCrossRefPubMedGoogle Scholar
  99. Pedram, A., Razandi, M., O’mahony, F., Harvey, H., Harvey, B. J., & Levin, E. R. (2013). Estrogen reduces lipid content in the liver exclusively from membrane receptor signaling. Science Signaling, 6, ra36.CrossRefPubMedGoogle Scholar
  100. Pedram, A., Razandi, M., Lewis, M., Hammes, S., & Levin, E. R. (2014). Membrane-localized estrogen receptor alpha is required for normal organ development and function. Developmental Cell, 29, 482–490.PubMedCentralCrossRefPubMedGoogle Scholar
  101. Pedram, A., Razandi, M., Blumberg, B., & Levin, E. R. (2016). Membrane and nuclear estrogen receptor alpha collaborate to suppress adipogenesis but not triglyceride content. The FASEB Journal, 30, 230–240.CrossRefPubMedGoogle Scholar
  102. Pendaries, C., Darblade, B., Rochaix, P., Krust, A., Chambon, P., Korach, K. S., Bayard, F., & Arnal, J. F. (2002). The AF-1 activation-function of ERalpha may be dispensable to mediate the effect of estradiol on endothelial NO production in mice. Proceedings of the National Academy of Sciences of the United States of America, 99, 2205–2210.PubMedCentralCrossRefPubMedGoogle Scholar
  103. Razandi, M., Pedram, A., Greene, G. L., & Levin, E. R. (1999). Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: Studies of ERalpha and ERbeta expressed in Chinese hamster ovary cells. Molecular Endocrinology, 13, 307–319.PubMedGoogle Scholar
  104. Reis, S. E., Gloth, S. T., Blumenthal, R. S., Resar, J. R., Zacur, H. A., Gerstenblith, G., & Brinker, J. A. (1994). Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women. Circulation, 89, 52–60.CrossRefPubMedGoogle Scholar
  105. Revankar, C. M., Cimino, D. F., Sklar, L. A., Arterburn, J. B., & Prossnitz, E. R. (2005). A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science, 307, 1625–1630.CrossRefPubMedGoogle Scholar
  106. Riant, E., Waget, A., Cogo, H., Arnal, J. F., Burcelin, R., & Gourdy, P. (2009). Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology, 150, 2109–2117.CrossRefPubMedGoogle Scholar
  107. Russell, K. S., Haynes, M. P., Sinha, D., Clerisme, E., & Bender, J. R. (2000). Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling. Proceedings of the National Academy of Sciences of the United States of America, 97, 5930–5935.PubMedCentralCrossRefPubMedGoogle Scholar
  108. Schwabe, J. W., Neuhaus, D., & Rhodes, D. (1990). Solution structure of the DNA-binding domain of the oestrogen receptor. Nature, 348, 458–461.CrossRefPubMedGoogle Scholar
  109. Simoncini, T., Hafezi-Moghadam, A., Brazil, D. P., Ley, K., Chin, W. W., & Liao, J. K. (2000). Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature, 407, 538–541.PubMedCentralCrossRefPubMedGoogle Scholar
  110. Smith, E. P., Boyd, J., Frank, G. R., Takahashi, H., Cohen, R. M., Specker, B., Williams, T. C., Lubahn, D. B., & Korach, K. S. (1994). Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. The New England Journal of Medicine, 331, 1056–1061.CrossRefPubMedGoogle Scholar
  111. Stefano, G. B., Prevot, V., Beauvillain, J. C., Cadet, P., Fimiani, C., Welters, I., Fricchione, G. L., Breton, C., Lassalle, P., Salzet, M., & Bilfinger, T. V. (2000). Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia. Circulation, 101, 1594–1597.CrossRefPubMedGoogle Scholar
  112. Thomas, C., & Gustafsson, J. A. (2011). The different roles of ER subtypes in cancer biology and therapy. Nature Reviews Cancer, 11, 597–608.CrossRefPubMedGoogle Scholar
  113. Tiano, J. P., & Mauvais-Jarvis, F. (2012a). Importance of oestrogen receptors to preserve functional beta-cell mass in diabetes. Nature Reviews. Endocrinology, 8, 342–351.CrossRefPubMedGoogle Scholar
  114. Tiano, J. P., & Mauvais-Jarvis, F. (2012b). Molecular mechanisms of estrogen receptors’ suppression of lipogenesis in pancreatic beta-cells. Endocrinology, 153, 2997–3005.PubMedCentralCrossRefPubMedGoogle Scholar
  115. Tiano, J. P., Delghingaro-Augusto, V., Le May, C., Liu, S., Kaw, M. K., Khuder, S. S., Latour, M. G., Bhatt, S. A., Korach, K. S., Najjar, S. M., Prentki, M., & Mauvais-Jarvis, F. (2011). Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents beta cell failure in rodent models of type 2 diabetes. The Journal of Clinical Investigation, 121, 3331–3342.PubMedCentralCrossRefPubMedGoogle Scholar
  116. Vinel, A., Hay, E., Valera, M. C., Buscato, M., Adlanmerini, M., Guillaume, M., Cohen-Solal, M., Ohlsson, C., Lenfant, F., Arnal, J. F., & Fontaine, C. (2016). Role of ERalpha in the effect of estradiol on cancellous and cortical femoral bone in growing female mice. Endocrinology, 157, 2533–2544.CrossRefPubMedGoogle Scholar
  117. Wedisinghe, L., & Perera, M. (2009). Diabetes and the menopause. Maturitas, 63, 200–203.CrossRefPubMedGoogle Scholar
  118. Wu, Q., Chambliss, K., Umetani, M., Mineo, C., & Shaul, P. W. (2011). Non-nuclear estrogen receptor signaling in the endothelium. The Journal of Biological Chemistry, 286, 14737–14743.PubMedCentralCrossRefPubMedGoogle Scholar
  119. Ylikomi, T., Bocquel, M. T., Berry, M., Gronemeyer, H., & Chambon, P. (1992). Cooperation of proto-signals for nuclear accumulation of estrogen and progesterone receptors. The EMBO Journal, 11, 3681–3694.PubMedCentralPubMedGoogle Scholar
  120. Zhou, J., Li, Y. S., & Chien, S. (2014). Shear stress-initiated signaling and its regulation of endothelial function. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 2191–2198.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Maeva Guillaume
    • 1
  • Alexandra Montagner
    • 1
  • Coralie Fontaine
    • 1
  • Françoise Lenfant
    • 1
  • Jean-François Arnal
    • 1
  • Pierre Gourdy
    • 1
  1. 1.I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM)-U 1048, Université de Toulouse 3 and CHU de ToulouseToulouseFrance

Personalised recommendations