Skip to main content
SpringerLink
Log in

The Role of Skeletal Muscle Estrogen Receptors in Metabolic Homeostasis and Insulin Sensitivity

  • Chapter
  • First Online:
Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1043))

Abstract

Women in the modern era are challenged with facing menopausal symptoms as well as heightened disease risk associated with increasing adiposity and metabolic dysfunction for up to three decades of life. Treatment strategies to combat metabolic dysfunction and associated pathologies have been hampered by our lack of understanding regarding the biological causes of these clinical conditions and our incomplete understanding regarding the effects of estrogens and the tissue-specific functions and molecular actions of its receptors. In this chapter we provide evidence supporting a critical and protective role for skeletal muscle estrogen receptor α in the maintenance of metabolic homeostasis and insulin sensitivity. Studies identifying the critical ER-regulated pathways essential for disease prevention will lay the important foundation for the rational design of novel therapeutic strategies to improve the health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Adams, J. M., 2nd, Pratipanawatr, T., Berria, R., Wang, E., DeFronzo, R. A., Sullards, M. C., & Mandarino, L. J. (2004). Ceramide content is increased in skeletal muscle from obese insulin-resistant humans. Diabetes, 53(1), 25–31.

    Article  CAS  PubMed  Google Scholar 

  • Alberti, K. G., Eckel, R. H., Grundy, S. M., Zimmet, P. Z., Cleeman, J. I., Donato, K. A., Fruchart, J. C., James, W. P., Loria, C. M., Smith, S. C., Jr., & International Diabetes Federation Task Force on E, Prevention, Hational Heart L, Blood I, American Heart A, World Heart F, International Atherosclerosis S, International Association for the Study of O. (2009). Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 120(16), 1640–1645. https://doi.org/10.1161/CIRCULATIONAHA.109.192644.

    Article  CAS  PubMed  Google Scholar 

  • Alonso, A., Ordonez, P., Fernandez, R., Moreno, M., Llaneza, P., Patterson, A. M., & Gonzalez, C. (2009). 17beta-estradiol treatment is unable to reproduce p85 alpha redistribution associated with gestational insulin resistance in rats. The Journal of Steroid Biochemistry and Molecular Biology, 116(3–5), 160–170. doi:S0960-0760(09)00164-2 [pii]. https://doi.org/10.1016/j.jsbmb.2009.05.010.

    Article  CAS  PubMed  Google Scholar 

  • Alonso, A., Gonzalez-Pardo, H., Garrido, P., Conejo, N. M., Llaneza, P., Diaz, F., Del Rey, C. G., & Gonzalez, C. (2010). Acute effects of 17 beta-estradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats. Age (Dordrecht, Netherlands), 32(4), 421–434. https://doi.org/10.1007/s11357-010-9148-6.

    Article  CAS  Google Scholar 

  • Amati, F., Dube, J. J., Alvarez-Carnero, E., Edreira, M. M., Chomentowski, P., Coen, P. M., Switzer, G. E., Bickel, P. E., Stefanovic-Racic, M., Toledo, F. G., & Goodpaster, B. H. (2011). Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: Another paradox in endurance-trained athletes? Diabetes, 60(10), 2588–2597. doi:db10-1221 [pii]. https://doi.org/10.2337/db10-1221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnal, J. F., Fontaine, C., Abot, A., Valera, M. C., Laurell, H., Gourdy, P., & Lenfant, F. (2013). Lessons from the dissection of the activation functions (AF-1 and AF-2) of the estrogen receptor alpha in vivo. Steroids, 78(6), 576–582. https://doi.org/10.1016/j.steroids.2012.11.011.

    Article  CAS  PubMed  Google Scholar 

  • Baltgalvis, K. A., Greising, S. M., Warren, G. L., & Lowe, D. A. (2010). Estrogen regulates estrogen receptors and antioxidant gene expression in mouse skeletal muscle. PLoS One, 5(4), e10164. https://doi.org/10.1371/journal.pone.0010164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banks, E. A., Brozinick, J. T., Jr., Yaspelkis, B. B., 3rd, Kang, H. Y., & Ivy, J. L. (1992). Muscle glucose transport, GLUT-4 content, and degree of exercise training in obese Zucker rats. The American Journal of Physiology, 263(5 Pt 1), E1010–E1015.

    CAS  PubMed  Google Scholar 

  • Barros, R. P., & Gustafsson, J. A. (2011). Estrogen receptors and the metabolic network. Cell Metabolism, 14(3), 289–299. doi:S1550-4131(11)00312-3 [pii]. https://doi.org/10.1016/j.cmet.2011.08.005.

    Article  CAS  PubMed  Google Scholar 

  • Barros, R. P. A., Machado, U. F., Warner, M., & Gustafsson, J.-Å. (2006). Muscle GLUT4 regulation by estrogen receptors ERβ and ERα. Proceedings of the National Academy of Sciences of the United States of America, 103(5), 1605–1608. https://doi.org/10.1073/pnas.0510391103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barros, R. P., Morani, A., Moriscot, A., & Machado, U. F. (2008). Insulin resistance of pregnancy involves estrogen-induced repression of muscle GLUT4. Molecular and Cellular Endocrinology, 295(1–2), 24–31. doi:S0303-7207(08)00286-4 [pii]. https://doi.org/10.1016/j.mce.2008.07.008.

    Article  CAS  PubMed  Google Scholar 

  • Befroy, D. E., Petersen, K. F., Dufour, S., Mason, G. F., de Graaf, R. A., Rothman, D. L., & Shulman, G. I. (2007). Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes, 56(5), 1376–1381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boland, R., Vasconsuelo, A., Milanesi, L., Ronda, A. C., & de Boland, A. R. (2008). 17beta-estradiol signaling in skeletal muscle cells and its relationship to apoptosis. Steroids, 73(9–10), 859–863. doi:S0039-128X(07)00258-9 [pii]. https://doi.org/10.1016/j.steroids.2007.12.027.

    Article  CAS  PubMed  Google Scholar 

  • 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(3), 459–468.

    Article  CAS  PubMed  Google Scholar 

  • Borras, C., Sastre, J., Garcia-Sala, D., Lloret, A., Pallardo, F. V., & Vina, J. (2003). Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radical Biology & Medicine, 34(5), 546–552. doi:S0891584902013564 [pii].

    Article  CAS  Google Scholar 

  • Brozinick, J. T., Jr., Etgen, G. J., Jr., Yaspelkis, B. B., 3rd, Kang, H. Y., & Ivy, J. L. (1993). Effects of exercise training on muscle GLUT-4 protein content and translocation in obese Zucker rats. The American Journal of Physiology, 265(3 Pt 1), E419–E427.

    CAS  PubMed  Google Scholar 

  • Brozinick, J. T., Jr., Etgen, G. J., Jr., Yaspelkis, B. B., 3rd, & Ivy, J. L. (1994). Glucose uptake and GLUT-4 protein distribution in skeletal muscle of the obese Zucker rat. The American Journal of Physiology, 267(1 Pt 2), R236–R243.

    CAS  PubMed  Google Scholar 

  • Bryzgalova, G., Gao, H., Ahren, B., Zierath, J. R., Galuska, D., Steiler, T. L., Dahlman-Wright, K., Nilsson, S., Gustafsson, J. A., Efendic, S., & Khan, A. (2006). Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: Insulin sensitivity in the liver. Diabetologia, 49(3), 588–597. https://doi.org/10.1007/s00125-005-0105-3.

    Article  CAS  PubMed  Google Scholar 

  • Campbell, S. E., & Febbraio, M. A. (2002). Effect of the ovarian hormones on GLUT4 expression and contraction-stimulated glucose uptake. American Journal of Physiology. Endocrinology and Metabolism, 282(5), E1139–E1146.

    Article  CAS  PubMed  Google Scholar 

  • Campbell, S. E., Mehan, K. A., Tunstall, R. J., Febbraio, M. A., & Cameron-Smith, D. (2003). 17beta-estradiol upregulates the expression of peroxisome proliferator-activated receptor alpha and lipid oxidative genes in skeletal muscle. Journal of Molecular Endocrinology, 31(1), 37–45.

    Article  CAS  PubMed  Google Scholar 

  • Casazza, K., Page, G. P., & Fernandez, J. R. (2010). The association between the rs2234693 and rs9340799 estrogen receptor alpha gene polymorphisms and risk factors for cardiovascular disease: A review. Biological Research for Nursing, 12(1), 84–97. doi:12/1/84 [pii]. https://doi.org/10.1177/1099800410371118.

    Article  CAS  PubMed  Google Scholar 

  • Charn, T. H., Liu, E. T., Chang, E. C., Lee, Y. K., Katzenellenbogen, J. A., & Katzenellenbogen, B. S. (2010). Genome-wide dynamics of chromatin binding of estrogen receptors alpha and beta: Mutual restriction and competitive site selection. Molecular Endocrinology, 24(1), 47–59. https://doi.org/10.1210/me.2009-0252.

  • Chen, J. Q., Delannoy, M., Cooke, C., & Yager, J. D. (2004). Mitochondrial localization of ERalpha and ERbeta in human MCF7 cells. American Journal of Physiology Endocrinology and Metabolism, 286(6), E1011–E1022.

    Article  CAS  PubMed  Google Scholar 

  • Chen, Z., Bassford, T., Green, S. B., Cauley, J. A., Jackson, R. D., LaCroix, A. Z., Leboff, M., Stefanick, M. L., & Margolis, K. L. (2005). Postmenopausal hormone therapy and body composition--a substudy of the estrogen plus progestin trial of the Women's Health Initiative. The American Journal of Clinical Nutrition, 82(3), 651–656. doi:82/3/651 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Choi, C. S., Fillmore, J. J., Kim, J. K., Liu, Z. X., Kim, S., Collier, E. F., Kulkarni, A., Distefano, A., Hwang, Y. J., Kahn, M., Chen, Y., Yu, C., Moore, I. K., Reznick, R. M., Higashimori, T., & Shulman, G. I. (2007). Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. The Journal of Clinical Investigation, 117(7), 1995–2003. https://doi.org/10.1172/JCI13579.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chung, S. S., Kim, M., Youn, B. S., Lee, N. S., Park, J. W., Lee, I. K., Lee, Y. S., Kim, J. B., Cho, Y. M., Lee, H. K., & Park, K. S. (2009). Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells. Molecular and Cellular Biology, 29(1), 20–30. doi:MCB.00544-08 [pii]. https://doi.org/10.1128/MCB.00544-08.

    Article  CAS  PubMed  Google Scholar 

  • Clemmensen, C., Muller, T. D., Finan, B., Tschop, M. H., & DiMarchi, R. (2016). Current and emerging treatment options in diabetes care. Handbook of Experimental Pharmacology, 233, 437–459. https://doi.org/10.1007/164_2015_7.

    Article  CAS  PubMed  Google Scholar 

  • 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(1–2), 147–154.

    Article  CAS  PubMed  Google Scholar 

  • Cornier, M. A., Dabelea, D., Hernandez, T. L., Lindstrom, R. C., Steig, A. J., Stob, N. R., Van Pelt, R. E., Wang, H., & Eckel, R. H. (2008). The metabolic syndrome. Endocrine Reviews, 29(7), 777–822. https://doi.org/10.1210/er.2008-0024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cortright, R. N., & Koves, T. R. (2000). Sex differences in substrate metabolism and energy homeostasis. Canadian Journal of Applied Physiology, 25(4), 288–311.

    Article  CAS  PubMed  Google Scholar 

  • Couse, J. F., & Korach, K. S. (1999). Estrogen receptor null mice: What have we learned and where will they lead us? Endocrine Reviews, 20(3), 358–417. https://doi.org/10.1210/edrv.20.3.0370.

    Article  CAS  PubMed  Google Scholar 

  • Couse, J. F., Curtis, S. W., Washburn, T. F., Eddy, E. M., Schomberg, D. W., & Korach, K. S. (1995). Disruption of the mouse oestrogen receptor gene: Resulting phenotypes and experimental findings. Biochemical Society Transactions, 23(4), 929–935.

    Article  CAS  PubMed  Google Scholar 

  • DeFronzo, R. A., Bonadonna, R. C., & Ferrannini, E. (1992). Pathogenesis of NIDDM. A balanced overview. Diabetes Care, 15(3), 318–368.

    Article  CAS  PubMed  Google Scholar 

  • Dela, F., Ploug, T., Handberg, A., Petersen, L. N., Larsen, J. J., Mikines, K. J., & Galbo, H. (1994). Physical training increases muscle GLUT4 protein and mRNA in patients with NIDDM. Diabetes, 43(7), 862–865.

    Article  CAS  PubMed  Google Scholar 

  • Deng, H. W., Li, J., Li, J. L., Dowd, R., Davies, K. M., Johnson, M., Gong, G., Deng, H., & Recker, R. R. (2000). Association of estrogen receptor-alpha genotypes with body mass index in normal healthy postmenopausal Caucasian women. The Journal of Clinical Endocrinology and Metabolism, 85(8), 2748–2751.

    CAS  PubMed  Google Scholar 

  • D'Eon, T. M., Rogers, N. H., Stancheva, Z. S., & Greenberg, A. S. (2008). Estradiol and the estradiol metabolite, 2-hydroxyestradiol, activate AMP-activated protein kinase in C2C12 myotubes. Obesity (Silver Spring), 16(6), 1284–1288. doi:oby200850 [pii]. https://doi.org/10.1038/oby.2008.50.

    Article  CAS  Google Scholar 

  • Dieli-Conwright, C. M., Spektor, T. M., Rice, J. C., Sattler, F. R., & Schroeder, E. T. (2009). Hormone therapy attenuates exercise-induced skeletal muscle damage in postmenopausal women. Journal of Applied Physiology, 107(3), 853–858. doi:00404.2009 [pii]. https://doi.org/10.1152/japplphysiol.00404.2009.

  • Ding, E. L., Song, Y., Manson, J. E., Rifai, N., Buring, J. E., & Liu, S. (2007). Plasma sex steroid hormones and risk of developing type 2 diabetes in women: A prospective study. Diabetologia, 50(10), 2076–2084. https://doi.org/10.1007/s00125-007-0785-y.

    Article  CAS  PubMed  Google Scholar 

  • Donath, M. Y., & Shoelson, S. E. (2011). Type 2 diabetes as an inflammatory disease. Nature Reviews. Immunology, 11(2), 98–107. doi:nri2925 [pii]. https://doi.org/10.1038/nri2925.

    Article  CAS  PubMed  Google Scholar 

  • Enns, D. L., & Tiidus, P. M. (2008). Estrogen influences satellite cell activation and proliferation following downhill running in rats. Journal of Applied Physiology, 104(2), 347–353. doi:00128.2007 [pii]. https://doi.org/10.1152/japplphysiol.00128.2007.

    Article  PubMed  Google Scholar 

  • Enns, D. L., Iqbal, S., & Tiidus, P. M. (2008). Oestrogen receptors mediate oestrogen-induced increases in post-exercise rat skeletal muscle satellite cells. Acta Physiologica (Oxford, England), 194(1), 81–93. doi:APS1861 [pii]. https://doi.org/10.1111/j.1748-1716.2008.01861.x.

    Article  CAS  Google Scholar 

  • Foryst-Ludwig, A., Clemenz, M., Hohmann, S., Hartge, M., Sprang, C., Frost, N., Krikov, M., Bhanot, S., Barros, R., Morani, A., Gustafsson, J. A., Unger, T., & Kintscher, U. (2008). Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genetics, 4(6), e1000108. https://doi.org/10.1371/journal.pgen.1000108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frias, J. P., Macaraeg, G. B., Ofrecio, J., Yu, J. G., Olefsky, J. M., & Kruszynska, Y. T. (2001). Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women. Diabetes, 50(6), 1344–1350.

    Article  CAS  PubMed  Google Scholar 

  • Fu, M. H., Maher, A. C., Hamadeh, M. J., Ye, C., & Tarnopolsky, M. A. (2009). Exercise, sex, menstrual cycle phase, and 17beta-estradiol influence metabolism-related genes in human skeletal muscle. Physiological Genomics, 40(1), 34–47. doi:00115.2009 [pii]. https://doi.org/10.1152/physiolgenomics.00115.2009.

    Article  CAS  PubMed  Google Scholar 

  • Furtado, L. M., Somwar, R., Sweeney, G., Niu, W., & Klip, A. (2002). Activation of the glucose transporter GLUT4 by insulin. Biochemistry and Cell Biology, 80(5), 569–578.

    Article  CAS  PubMed  Google Scholar 

  • Galluzzo, P., Rastelli, C., Bulzomi, P., Acconcia, F., Pallottini, V., & Marino, M. (2009). 17beta-Estradiol regulates the first steps of skeletal muscle cell differentiation via ER-alpha-mediated signals. American Journal of Physiology Cell Physiology, 297(5), C1249–C1262. doi:00188.2009 [pii]. https://doi.org/10.1152/ajpcell.00188.2009.

    Article  CAS  PubMed  Google Scholar 

  • Gan, Z., Burkart-Hartman, E. M., Han, D. H., Finck, B., Leone, T. C., Smith, E. Y., Ayala, J. E., Holloszy, J., & Kelly, D. P. (2011). The nuclear receptor PPARbeta/delta programs muscle glucose metabolism in cooperation with AMPK and MEF2. Genes & Development, 25(24), 2619–2630. doi:gad.178434.111 [pii]. https://doi.org/10.1101/gad.178434.111.

    Article  CAS  Google Scholar 

  • Garvey, W. T., Maianu, L., Hancock, J. A., Golichowski, A. M., & Baron, A. (1992). Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes, 41(4), 465–475.

    Article  CAS  PubMed  Google Scholar 

  • Garvey, W. T., Maianu, L., Zhu, J. H., Brechtel-Hook, G., Wallace, P., & Baron, A. D. (1998). Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. The Journal of Clinical Investigation, 101(11), 2377–2386. https://doi.org/10.1172/JCI1557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gomez-Perez, Y., Amengual-Cladera, E., Catala-Niell, A., Thomas-Moya, E., Gianotti, M., Proenza, A. M., & Llado, I. (2008). Gender dimorphism in high-fat-diet-induced insulin resistance in skeletal muscle of aged rats. Cellular Physiology and Biochemistry, 22(5–6), 539–548. doi:000185538 [pii]. https://doi.org/10.1159/000185538.

    Article  CAS  PubMed  Google Scholar 

  • Gong, H., Xie, J., Zhang, N., Yao, L., & Zhang, Y. (2011). MEF2A binding to the Glut4 promoter occurs via an AMPKalpha2-dependent mechanism. Medicine and Science in Sports and Exercise, 43(8), 1441–1450. https://doi.org/10.1249/MSS.0b013e31820f6093.

    Article  CAS  PubMed  Google Scholar 

  • Gorres, B. K., Bomhoff, G. L., Morris, J. K., & Geiger, P. C. (2011). In vivo stimulation of oestrogen receptor alpha increases insulin-stimulated skeletal muscle glucose uptake. The Journal of Physiology, 589(Pt 8), 2041–2054. https://doi.org/10.1113/jphysiol.2010.199018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green, S., Walter, P., Greene, G., Krust, A., Goffin, C., Jensen, E., Scrace, G., Waterfield, M., & Chambon, P. (1986). Cloning of the human oestrogen receptor cDNA. Journal of Steroid Biochemistry, 24(1), 77–83.

    Article  CAS  PubMed  Google Scholar 

  • Guercio, G., Di Palma, M. I., Pepe, C., Saraco, N. I., Prieto, M., Saure, C., Mazza, C., Rivarola, M. A., & Belgorosky, A. (2009). Metformin, estrogen replacement therapy and gonadotropin inhibition fail to improve insulin sensitivity in a girl with aromatase deficiency. Hormone Research, 72(6), 370–376. doi:000249165 [pii]. https://doi.org/10.1159/000249165.

    Article  CAS  PubMed  Google Scholar 

  • Hamadeh, M. J., Devries, M. C., & Tarnopolsky, M. A. (2005). Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise. The Journal of Clinical Endocrinology and Metabolism, 90(6), 3592–3599. doi:jc.2004-1743 [pii]. https://doi.org/10.1210/jc.2004-1743.

    Article  CAS  PubMed  Google Scholar 

  • Hamilton, D. J., Minze, L. J., Kumar, T., Cao, T. N., Lyon, C. J., Geiger, P. C., Hsueh, W. A., & Gupte, A. A. (2016). Estrogen receptor alpha activation enhances mitochondrial function and systemic metabolism in high-fat-fed ovariectomized mice. Physiological Reports, 4(17). https://doi.org/10.14814/phy2.12913.

  • Hammes, S. R., & Levin, E. R. (2007). Extranuclear steroid receptors: Nature and actions. Endocrine Reviews, 28(7), 726–741.

    Article  CAS  PubMed  Google Scholar 

  • Hansen, P. A., McCarthy, T. J., Pasia, E. N., Spina, R. J., & Gulve, E. A. (1996). Effects of ovariectomy and exercise training on muscle GLUT-4 content and glucose metabolism in rats. Journal of Applied Physiology, 80(5), 1605–1611.

    Article  CAS  PubMed  Google Scholar 

  • Hardie, D. G. (2011). AMP-activated protein kinase: An energy sensor that regulates all aspects of cell function. Genes & Development, 25(18), 1895–1908. doi:25/18/1895 [pii]. https://doi.org/10.1101/gad.17420111.

    Article  CAS  Google Scholar 

  • 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(23), 12729–12734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hevener, A. L., Reichart, D., & Olefsky, J. (2000). Exercise and thiazolidinedione therapy normalize insulin action in the obese Zucker fatty rat. Diabetes, 49(12), 2154–2159.

    Article  CAS  PubMed  Google Scholar 

  • Hevener, A., Reichart, D., Janez, A., & Olefsky, J. (2002). Female rats do not exhibit free fatty acid-induced insulin resistance. Diabetes, 51(6), 1907–1912.

    Article  CAS  PubMed  Google Scholar 

  • Hevener, A. L., Olefsky, J. M., Reichart, D., Nguyen, M. T., Bandyopadyhay, G., Leung, H. Y., Watt, M. J., Benner, C., Febbraio, M. A., Nguyen, A. K., Folian, B., Subramaniam, S., Gonzalez, F. J., Glass, C. K., & Ricote, M. (2007). Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. The Journal of Clinical Investigation, 117(6), 1658–1669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoeg, L., Roepstorff, C., Thiele, M., Richter, E. A., Wojtaszewski, J. F., & Kiens, B. (2009). Higher intramuscular triacylglycerol in women does not impair insulin sensitivity and proximal insulin signaling. Journal of Applied Physiology, 107(3), 824–831. doi:91382.2008 [pii]. https://doi.org/10.1152/japplphysiol.91382.2008.

    Article  CAS  PubMed  Google Scholar 

  • Hoeg, L. D., Sjoberg, K. A., Jeppesen, J., Jensen, T. E., Frosig, C., Birk, J. B., Bisiani, B., Hiscock, N., Pilegaard, H., Wojtaszewski, J. F., Richter, E. A., & Kiens, B. (2011). Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. Diabetes, 60(1), 64–73. doi:db10-0698 [pii]. https://doi.org/10.2337/db10-0698.

    Article  CAS  PubMed  Google Scholar 

  • Holland, W. L., Brozinick, J. T., Wang, L. P., Hawkins, E. D., Sargent, K. M., Liu, Y., Narra, K., Hoehn, K. L., Knotts, T. A., Siesky, A., Nelson, D. H., Karathanasis, S. K., Fontenot, G. K., Birnbaum, M. J., & Summers, S. A. (2007a). Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metabolism, 5(3), 167–179.

    Article  CAS  PubMed  Google Scholar 

  • Holland, W. L., Knotts, T. A., Chavez, J. A., Wang, L. P., Hoehn, K. L., & Summers, S. A. (2007b). Lipid mediators of insulin resistance. Nutrition Reviews, 65(6 Pt 2), S39–S46.

    Article  PubMed  Google Scholar 

  • Hotamisligil, G. S. (2008). Inflammation and endoplasmic reticulum stress in obesity and diabetes. International Journal of Obesity, 32(Suppl 7), S52–S54. doi:ijo2008238 [pii]. https://doi.org/10.1038/ijo.2008.238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itani, S. I., Ruderman, N. B., Schmieder, F., & Boden, G. (2002). Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes, 51(7), 2005–2011.

    Article  CAS  PubMed  Google Scholar 

  • Jensen, E. V., Jacobson, H. I., Walf, A. A., & Frye, C. A. (2010). Estrogen action: A historic perspective on the implications of considering alternative approaches. Physiology & Behavior, 99(2), 151–162. https://doi.org/10.1016/j.physbeh.2009.08.013.

    Article  CAS  Google Scholar 

  • Jia, M., Dahlman-Wright, K., & Gustafsson, J. A. (2015). Estrogen receptor alpha and beta in health and disease. Best Practice & Research Clinical Endocrinology & Metabolism, 29(4), 557–568. https://doi.org/10.1016/j.beem.2015.04.008.

    Article  CAS  Google Scholar 

  • 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(23), 12735–12740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jones, M. E., McInnes, K. J., Boon, W. C., & Simpson, E. R. (2007). Estrogen and adiposity–utilizing models of aromatase deficiency to explore the relationship. The Journal of Steroid Biochemistry and Molecular Biology, 106(1–5), 3–7. doi:S0960-0760(07)00106-9 [pii]. https://doi.org/10.1016/j.jsbmb.2007.05.029.

    Article  CAS  PubMed  Google Scholar 

  • Kalyani, R. R., Franco, M., Dobs, A. S., Ouyang, P., Vaidya, D., Bertoni, A., Gapstur, S. M., & Golden, S. H. (2009). The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. The Journal of Clinical Endocrinology and Metabolism, 94(11), 4127–4135. doi:jc.2009-0910 [pii]. https://doi.org/10.1210/jc.2009-0910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamanga-Sollo, E., White, M. E., Hathaway, M. R., Weber, W. J., & Dayton, W. R. (2010). Effect of Estradiol-17beta on protein synthesis and degradation rates in fused bovine satellite cell cultures. Domestic Animal Endocrinology, 39(1), 54–62. doi:S0739-7240(10)00009-3 [pii]. https://doi.org/10.1016/j.domaniend.2010.02.002.

    Article  CAS  PubMed  Google Scholar 

  • 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), 1–9.

    Article  CAS  PubMed  Google Scholar 

  • Kim, J. Y., Jo, K. J., Kim, O. S., Kim, B. J., Kang, D. W., Lee, K. H., Baik, H. W., Han, M. S., & Lee, S. K. (2010). Parenteral 17beta-estradiol decreases fasting blood glucose levels in non-obese mice with short-term ovariectomy. Life Sciences, 87(11–12), 358–366. doi:S0024-3205(10)00316-4 [pii]. https://doi.org/10.1016/j.lfs.2010.07.009.

    Article  CAS  PubMed  Google Scholar 

  • Kuiper, G. G., Enmark, E., Pelto-Huikko, M., Nilsson, S., & Gustafsson, J. A. (1996). Cloning of a novel receptor expressed in rat prostate and ovary. Proceedings of the National Academy of Sciences of the United States of America, 93(12), 5925–5930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuiper, G. G., Carlsson, B., Grandien, K., Enmark, E., Haggblad, J., Nilsson, S., & Gustafsson, J. A. (1997). Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology, 138(3), 863–870.

    Article  CAS  PubMed  Google Scholar 

  • Lee, Y. R., Park, J., Yu, H. N., Kim, J. S., Youn, H. J., & Jung, S. H. (2005). Up-regulation of PI3K/Akt signaling by 17beta-estradiol through activation of estrogen receptor-alpha, but not estrogen receptor-beta, and stimulates cell growth in breast cancer cells. Biochemical and Biophysical Research Communications, 336(4), 1221–1226. doi:S0006-291X(05)01972-8 [pii]. https://doi.org/10.1016/j.bbrc.2005.08.256.

    Article  CAS  PubMed  Google Scholar 

  • Leger, B., Derave, W., De Bock, K., Hespel, P., & Russell, A. P. (2008). Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylation. Rejuvenation Research, 11(1), 163–175B. https://doi.org/10.1089/rej.2007.0588.

    Article  CAS  PubMed  Google Scholar 

  • Lemoine, S., Granier, P., Tiffoche, C., Berthon, P. M., Rannou-Bekono, F., Thieulant, M. L., Carre, F., & Delamarche, P. (2002a). Effect of endurance training on oestrogen receptor alpha transcripts in rat skeletal muscle. Acta Physiologica Scandinavica, 174(3), 283–289. doi:943 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Lemoine, S., Granier, P., Tiffoche, C., Berthon, P. M., Thieulant, M. L., Carre, F., & Delamarche, P. (2002b). Effect of endurance training on oestrogen receptor alpha expression in different rat skeletal muscle type. Acta Physiologica Scandinavica, 175(3), 211–217. doi:992 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Levin, E. R. (2015). Extranuclear steroid receptors are essential for steroid hormone actions. Annual Review of Medicine, 66, 271–280. https://doi.org/10.1146/annurev-med-050913-021703.

    Article  CAS  PubMed  Google Scholar 

  • Lewis, S. C., Uchiyama, L. F., & Nunnari, J. (2016). ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science, 353(6296), aaf5549. https://doi.org/10.1126/science.aaf5549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liao, S. (1975). Cellular receptors and mechanisms of action of steroid hormones. International Review of Cytology, 41, 87–172.

    Article  CAS  PubMed  Google Scholar 

  • Lipovka, Y., Chen, H., Vagner, J., Price, T. J., Tsao, T. S., & Konhilas, J. P. (2015). Oestrogen receptors interact with the alpha-catalytic subunit of AMP-activated protein kinase. Bioscience Reports, 35(5). https://doi.org/10.1042/BSR20150074.

  • Liu, S., & Mauvais-Jarvis, F. (2010). Minireview: Estrogenic protection of beta-cell failure in metabolic diseases. Endocrinology, 151(3), 859–864. https://doi.org/10.1210/en.2009-1107.

    Article  CAS  PubMed  Google Scholar 

  • Maffei, L., Murata, Y., Rochira, V., Tubert, G., Aranda, C., Vazquez, M., Clyne, C. D., Davis, S., Simpson, E. R., & Carani, C. (2004). Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: Effects of testosterone, alendronate, and estradiol treatment. The Journal of Clinical Endocrinology and Metabolism, 89(1), 61–70.

    Article  CAS  PubMed  Google Scholar 

  • Maffei, L., Rochira, V., Zirilli, L., Antunez, P., Aranda, C., Fabre, B., Simone, M. L., Pignatti, E., Simpson, E. R., Houssami, S., Clyne, C. D., & Carani, C. (2007). A novel compound heterozygous mutation of the aromatase gene in an adult man: Reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome. Clinical Endocrinology, 67(2), 218–224. doi:CEN2864 [pii]. https://doi.org/10.1111/j.1365-2265.2007.02864.x.

    Article  CAS  PubMed  Google Scholar 

  • Maher, A. C., Akhtar, M., & Tarnopolsky, M. A. (2010a). Men supplemented with 17beta-estradiol have increased beta-oxidation capacity in skeletal muscle. Physiological Genomics, 42(3), 342–347. doi:physiolgenomics.00016.2010 [pii]. https://doi.org/10.1152/physiolgenomics.00016.2010.

    Article  CAS  PubMed  Google Scholar 

  • Maher, A. C., Akhtar, M., Vockley, J., & Tarnopolsky, M. A. (2010b). Women have higher protein content of beta-oxidation enzymes in skeletal muscle than men. PLoS One, 5(8), e12025. https://doi.org/10.1371/journal.pone.0012025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mannella, P., & Brinton, R. D. (2006). Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: A unified mechanism of estrogen action. The Journal of Neuroscience, 26(37), 9439–9447. doi:26/37/9439 [pii]. https://doi.org/10.1523/JNEUROSCI.1443-06.2006.

    Article  CAS  PubMed  Google Scholar 

  • 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(7), 1175–1187.

    Article  CAS  PubMed  Google Scholar 

  • 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(3), 173–188. https://doi.org/10.1210/er.2016-1146.

    Article  PubMed  Google Scholar 

  • McLoughlin, T. J., Smith, S. M., DeLong, A. D., Wang, H., Unterman, T. G., & Esser, K. A. (2009). FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner. American Journal of Physiology. Cell Physiology, 297(3), C548–C555. doi:00502.2008 [pii]. https://doi.org/10.1152/ajpcell.00502.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Messier, V., Rabasa-Lhoret, R., Barbat-Artigas, S., Elisha, B., Karelis, A. D., & Aubertin-Leheudre, M. (2011). Menopause and sarcopenia: A potential role for sex hormones. Maturitas, 68(4), 331–336. doi:S0378-5122(11)00030-2 [pii]. https://doi.org/10.1016/j.maturitas.2011.01.014.

    Article  CAS  PubMed  Google Scholar 

  • Mihaylova, M. M., & Shaw, R. J. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature Cell Biology, 13(9), 1016–1023. doi:ncb2329 [pii]. https://doi.org/10.1038/ncb2329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miranda, P. J., DeFronzo, R. A., Califf, R. M., & Guyton, J. R. (2005). Metabolic syndrome: Definition, pathophysiology, and mechanisms. American Heart Journal, 149(1), 33–45. doi:S0002870304004491 [pii]. https://doi.org/10.1016/j.ahj.2004.07.013.

    Article  CAS  PubMed  Google Scholar 

  • Mora, S., & Pessin, J. E. (2000). The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. The Journal of Biological Chemistry, 275(21), 16323–16328. https://doi.org/10.1074/jbc.M910259199. M910259199 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Moreno, H., Serrano, A. L., Santalucia, T., Guma, A., Canto, C., Brand, N. J., Palacin, M., Schiaffino, S., & Zorzano, A. (2003). Differential regulation of the muscle-specific GLUT4 enhancer in regenerating and adult skeletal muscle. The Journal of Biological Chemistry, 278(42), 40557–40564. https://doi.org/10.1074/jbc.M306609200. M306609200 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Morino, K., Petersen, K. F., Dufour, S., Befroy, D., Frattini, J., Shatzkes, N., Neschen, S., White, M. F., Bilz, S., Sono, S., Pypaert, M., & Shulman, G. I. (2005). Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. The Journal of Clinical Investigation, 115(12), 3587–3593. https://doi.org/10.1172/JCI25151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(12), 3689–3698.

    CAS  PubMed  Google Scholar 

  • Murgia, M., Jensen, T. E., Cusinato, M., Garcia, M., Richter, E. A., & Schiaffino, S. (2009). Multiple signalling pathways redundantly control glucose transporter GLUT4 gene transcription in skeletal muscle. The Journal of Physiology, 587(17), 4319–4327. https://doi.org/10.1113/jphysiol.2009.174888.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Naaz, A., Zakroczymski, M., Heine, P., Taylor, J., Saunders, P., Lubahn, D., & Cooke, P. S. (2002). Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): A potential role for estrogen receptor beta (ERbeta). Hormone and Metabolic Research, 34(11–12), 758–763.

    Article  CAS  PubMed  Google Scholar 

  • 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(1–2), 63–68. https://doi.org/10.1016/j.mce.2009.02.016.

    Article  CAS  PubMed  Google Scholar 

  • Nilsson, S., Makela, S., Treuter, E., Tujague, M., Thomsen, J., Andersson, G., Enmark, E., Pettersson, K., Warner, M., & Gustafsson, J. A. (2001). Mechanisms of estrogen action. Physiological Reviews, 81(4), 1535–1565.

    Article  CAS  PubMed  Google Scholar 

  • Nilsson, M., Dahlman, I., Ryden, M., Nordstrom, E. A., Gustafsson, J. A., Arner, P., & Dahlman-Wright, K. (2007). Oestrogen receptor alpha gene expression levels are reduced in obese compared to normal weight females. International Journal of Obesity, 31(6), 900–907. doi:0803528 [pii]. https://doi.org/10.1038/sj.ijo.0803528.

    Article  CAS  PubMed  Google Scholar 

  • Niu, W., Huang, C., Nawaz, Z., Levy, M., Somwar, R., Li, D., Bilan, P. J., & Klip, A. (2003). Maturation of the regulation of GLUT4 activity by p38 MAPK during L6 cell myogenesis. The Journal of Biological Chemistry, 278(20), 17953–17962. https://doi.org/10.1074/jbc.M211136200. M211136200 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Noh, E. M., Lee, Y. R., Chay, K. O., Chung, E. Y., Jung, S. H., Kim, J. S., & Youn, H. J. (2011). Estrogen receptor alpha induces down-regulation of PTEN through PI3-kinase activation in breast cancer cells. Molecular Medicine Report, 4(2), 215–219. https://doi.org/10.3892/mmr.2011.412.

    CAS  Google Scholar 

  • North American Menopause Society. (2012). The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause, 19(3), 257–271. https://doi.org/10.1097/gme.0b013e31824b970a.

    Article  Google Scholar 

  • O’Malley, B. W. (1971). Mechanisms of action of steroid hormones. The New England Journal of Medicine, 284(7), 370–377. https://doi.org/10.1056/NEJM197102182840710.

    Article  PubMed  Google Scholar 

  • Ohlsson, C., Hellberg, N., Parini, P., Vidal, O., Bohlooly, Y. M., Rudling, M., Lindberg, M. K., Warner, M., Angelin, B., & Gustafsson, J. A. (2000). Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochemical and Biophysical Research Communications, 278(3), 640–645. https://doi.org/10.1006/bbrc.2000.3827. S0006-291X(00)93827-0 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Okura, T., Koda, M., Ando, F., Niino, N., Ohta, S., & Shimokata, H. (2003a). Association of polymorphisms in the estrogen receptor alpha gene with body fat distribution. International Journal of Obesity and Related Metabolic Disorders, 27(9), 1020–1027.

    Article  CAS  PubMed  Google Scholar 

  • Okura, T., Koda, M., Ando, F., Niino, N., & Shimokata, H. (2003b). Relationships of resting energy expenditure with body fat distribution and abdominal fatness in Japanese population. Journal of Physiological Anthropology and Applied Human Science, 22(1), 47–52.

    Article  PubMed  Google Scholar 

  • Okura, T., Koda, M., Ando, F., Niino, N., Tanaka, M., & Shimokata, H. (2003c). Association of the mitochondrial DNA 15497G/A polymorphism with obesity in a middle-aged and elderly Japanese population. Human Genetics, 113(5), 432–436.

    Article  CAS  PubMed  Google Scholar 

  • Ordonez, P., Moreno, M., Alonso, A., Llaneza, P., Diaz, F., & Gonzalez, C. (2008). 17beta-Estradiol and/or progesterone protect from insulin resistance in STZ-induced diabetic rats. The Journal of Steroid Biochemistry and Molecular Biology, 111(3–5), 287–294. doi:S0960-0760(08)00190-8 [pii]. https://doi.org/10.1016/j.jsbmb.2008.07.001.

    Article  CAS  PubMed  Google Scholar 

  • Oshel, K. M., Knight, J. B., Cao, K. T., Thai, M. V., & Olson, A. L. (2000). Identification of a 30-base pair regulatory element and novel DNA binding protein that regulates the human GLUT4 promoter in transgenic mice. The Journal of Biological Chemistry, 275(31), 23666–23673. https://doi.org/10.1074/jbc.M001452200. M001452200 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Park, Y. W., Zhu, S., Palaniappan, L., Heshka, S., Carnethon, M. R., & Heymsfield, S. B. (2003). The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Archives of Internal Medicine, 163(4), 427–436.

    Article  PubMed  PubMed Central  Google Scholar 

  • Patti, M. E., Butte, A. J., Crunkhorn, S., Cusi, K., Berria, R., Kashyap, S., Miyazaki, Y., Kohane, I., Costello, M., Saccone, R., Landaker, E. J., Goldfine, A. B., Mun, E., DeFronzo, R., Finlayson, J., Kahn, C. R., & Mandarino, L. J. (2003). Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proceedings of the National Academy of Sciences of the United States of America, 100(14), 8466–8471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(1), 230–240. https://doi.org/10.1096/fj.15-274878.

    Article  CAS  PubMed  Google Scholar 

  • Pentti, K., Tuppurainen, M. T., Honkanen, R., Sandini, L., Kroger, H., Alhava, E., & Saarikoski, S. (2009). Hormone therapy protects from diabetes: The Kuopio osteoporosis risk factor and prevention study. European Journal of Endocrinology, 160(6), 979–983. https://doi.org/10.1530/EJE-09-0151.

    Article  CAS  PubMed  Google Scholar 

  • Petersen, K. F., Dufour, S., Befroy, D., Garcia, R., & Shulman, G. I. (2004). Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. The New England Journal of Medicine, 350(7), 664–671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(5), 2109–2117.

    Article  CAS  PubMed  Google Scholar 

  • Ribas, V., Drew, B. G., Soleymani, T., Daraei, P., & Hevener, A. (2010a). Skeletal muscle specific ER alpha deletion is causal for the metabolic syndrome. Endocrine Reviews, 31(3), S5.

    Google Scholar 

  • Ribas, V., Nguyen, M. T., Henstridge, D. C., Nguyen, A. K., Beaven, S. W., Watt, M. J., & Hevener, A. L. (2010b). Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice. American Journal of Physiology. Endocrinology and Metabolism, 298(2), E304–E319. https://doi.org/10.1152/ajpendo.00504.2009.

    Article  CAS  PubMed  Google Scholar 

  • Ribas, V., Drew, B. G., Zhou, Z., Phun, J., Kalajian, N. Y., Soleymani, T., Daraei, P., Widjaja, K., Wanagat, J., de Aguiar Vallim, T. Q., Fluitt, A. H., Bensinger, S., Le, T., Radu, C., Whitelegge, J. P., Beaven, S. W., Tontonoz, P., Lusis, A. J., Parks, B. W., Vergnes, L., Reue, K., Singh, H., Bopassa, J. C., Toro, L., Stefani, E., Watt, M. J., Schenk, S., Akerstrom, T., Kelly, M., Pedersen, B. K., Hewitt, S. C., Korach, K. S., & Hevener, A. L. (2016). Skeletal muscle action of estrogen receptor alpha is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Science Translational Medicine, 8(334), 334ra354. https://doi.org/10.1126/scitranslmed.aad3815.

    Article  CAS  Google Scholar 

  • Rochira, V., Madeo, B., Zirilli, L., Caffagni, G., Maffei, L., & Carani, C. (2007). Oestradiol replacement treatment and glucose homeostasis in two men with congenital aromatase deficiency: Evidence for a role of oestradiol and sex steroids imbalance on insulin sensitivity in men. Diabetic Medicine, 24(12), 1491–1495. doi:DME2304 [pii]. https://doi.org/10.1111/j.1464-5491.2007.02304.x.

    Article  CAS  PubMed  Google Scholar 

  • Rodnick, K. J., Holloszy, J. O., Mondon, C. E., & James, D. E. (1990). Effects of exercise training on insulin-regulatable glucose-transporter protein levels in rat skeletal muscle. Diabetes, 39(11), 1425–1429.

    Article  CAS  PubMed  Google Scholar 

  • Rogers, N. H., Witczak, C. A., Hirshman, M. F., Goodyear, L. J., & Greenberg, A. S. (2009). Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochemical and Biophysical Research Communications, 382(4), 646–650. doi:S0006-291X(09)00441-0 [pii]. https://doi.org/10.1016/j.bbrc.2009.02.154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ronda, A. C., & Boland, R. L. (2016). Intracellular distribution and involvement of GPR30 in the actions of E2 on C2C12 cells. Journal of Cellular Biochemistry, 117(3), 793–805. https://doi.org/10.1002/jcb.25369.

    Article  CAS  PubMed  Google Scholar 

  • Ronda, A. C., Buitrago, C., & Boland, R. (2010a). Role of estrogen receptors, PKC and Src in ERK2 and p38 MAPK signaling triggered by 17beta-estradiol in skeletal muscle cells. The Journal of Steroid Biochemistry and Molecular Biology, 122(4), 287–294. doi:S0960-0760(10)00234-7 [pii]. https://doi.org/10.1016/j.jsbmb.2010.05.002.

    Article  CAS  PubMed  Google Scholar 

  • Ronda, A. C., Vasconsuelo, A., & Boland, R. (2010b). Extracellular-regulated kinase and p38 mitogen-activated protein kinases are involved in the antiapoptotic action of 17beta-estradiol in skeletal muscle cells. The Journal of Endocrinology, 206(2), 235–246. doi:JOE-09-0429 [pii]. https://doi.org/10.1677/JOE-09-0429.

    Article  CAS  PubMed  Google Scholar 

  • Safe, S., & Kim, K. (2008). Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. Journal of Molecular Endocrinology, 41(5), 263–275. https://doi.org/10.1677/JME-08-0103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Salehzadeh, F., Rune, A., Osler, M., & Al-Khalili, L. (2011). Testosterone or 17{beta}-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes. The Journal of Endocrinology, 210(2), 219–229. doi:JOE-10-0497 [pii]. https://doi.org/10.1530/JOE-10-0497.

    Article  CAS  PubMed  Google Scholar 

  • Salpeter, S. R., Walsh, J. M., Ormiston, T. M., Greyber, E., Buckley, N. S., & Salpeter, E. E. (2006). Meta-analysis: Effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obesity & Metabolism, 8(5), 538–554.

    Article  CAS  Google Scholar 

  • Shang, Y., Hu, X., DiRenzo, J., Lazar, M. A., & Brown, M. (2000). Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell, 103(6), 843–852.

    Article  CAS  PubMed  Google Scholar 

  • 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(6803), 538–541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simoncini, T., Fornari, L., Mannella, P., Varone, G., Caruso, A., Liao, J. K., & Genazzani, A. R. (2002). Novel non-transcriptional mechanisms for estrogen receptor signaling in the cardiovascular system. Interaction of estrogen receptor alpha with phosphatidylinositol 3-OH kinase. Steroids, 67(12), 935–939. doi:S0039128X02000405 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Sipila, S., Taaffe, D. R., Cheng, S., Puolakka, J., Toivanen, J., & Suominen, H. (2001). Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in post-menopausal women: A randomized placebo-controlled study. Clinical Science (London, England), 101(2), 147–157.

    Article  CAS  Google Scholar 

  • 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(16), 1056–1061.

    Article  CAS  PubMed  Google Scholar 

  • Smith, J. A., Kohn, T. A., Chetty, A. K., & Ojuka, E. O. (2008). CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the MEF2 site on the Glut4 gene. American Journal of Physiology. Endocrinology and Metabolism, 295(3), E698–E704. doi:00747.2007 [pii]. https://doi.org/10.1152/ajpendo.00747.2007.

    Article  CAS  PubMed  Google Scholar 

  • Sorensen, M. B., Rosenfalck, A. M., Hojgaard, L., & Ottesen, B. (2001). Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy. Obesity Research, 9(10), 622–626. https://doi.org/10.1038/oby.2001.81.

    Article  CAS  PubMed  Google Scholar 

  • Sotiriadou, S., Kyparos, A., Albani, M., Arsos, G., Clarke, M. S., Sidiras, G., Angelopoulou, N., & Matziari, C. (2006). Soleus muscle force following downhill running in ovariectomized rats treated with estrogen. Applied Physiology, Nutrition, and Metabolism, 31(4), 449–459. doi:h06-008 [pii]. https://doi.org/10.1139/h06-008.

    Article  CAS  PubMed  Google Scholar 

  • Stitt, T. N., Drujan, D., Clarke, B. A., Panaro, F., Timofeyva, Y., Kline, W. O., Gonzalez, M., Yancopoulos, G. D., & Glass, D. J. (2004). The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FOXO transcription factors. Molecular Cell, 14(3), 395–403. doi:S1097276504002114 [pii].

    Article  CAS  PubMed  Google Scholar 

  • Stubbins, R. E., Holcomb, V. B., Hong, J., & Nunez, N. P. (2011). Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. European Journal of Nutrition. https://doi.org/10.1007/s00394-011-0266-4.

  • Summers, S. A. (2006). Ceramides in insulin resistance and lipotoxicity. Progress in Lipid Research, 45(1), 42–72. doi:S0163-7827(05)00050-0 [pii]. https://doi.org/10.1016/j.plipres.2005.11.002.

    Article  CAS  PubMed  Google Scholar 

  • Sweeney, G., Somwar, R., Ramlal, T., Volchuk, A., Ueyama, A., & Klip, A. (1999). An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. The Journal of Biological Chemistry, 274(15), 10071–10078.

    Article  CAS  PubMed  Google Scholar 

  • Szmuilowicz, E. D., Stuenkel, C. A., & Seely, E. W. (2009). Influence of menopause on diabetes and diabetes risk. Nature Reviews Endocrinology, 5(10), 553–558. https://doi.org/10.1038/nrendo.2009.166.

    Article  PubMed  Google Scholar 

  • Takeda, K., Toda, K., Saibara, T., Nakagawa, M., Saika, K., Onishi, T., Sugiura, T., & Shizuta, Y. (2003). Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. The Journal of Endocrinology, 176(2), 237–246.

    Article  CAS  PubMed  Google Scholar 

  • Teixeira, P. J., Going, S. B., Houtkooper, L. B., Metcalfe, L. L., Blew, R. M., Flint-Wagner, H. G., Cussler, E. C., Sardinha, L. B., & Lohman, T. G. (2003). Resistance training in postmenopausal women with and without hormone therapy. Medicine and Science in Sports and Exercise, 35(4), 555–562. https://doi.org/10.1249/01.MSS.0000058437.17262.11.

    Article  PubMed  Google Scholar 

  • Thomas, A., Bunyan, K., & Tiidus, P. M. (2010). Oestrogen receptor-alpha activation augments post-exercise myoblast proliferation. Acta Physiologica (Oxford, England), 198(1), 81–89. doi:APS2033 [pii]. https://doi.org/10.1111/j.1748-1716.2009.02033.x.

    Article  CAS  Google Scholar 

  • Tiano, J. P., & Mauvais-Jarvis, F. (2012). Importance of oestrogen receptors to preserve functional beta-cell mass in diabetes. Nature Reviews Endocrinology. https://doi.org/10.1038/nrendo.2011.242.

  • Tiidus, P. M. (2000). Estrogen and gender effects on muscle damage, inflammation, and oxidative stress. Canadian Journal of Applied Physiology, 25(4), 274–287.

    Article  CAS  PubMed  Google Scholar 

  • Turcotte, L. P., Richter, E. A., & Kiens, B. (1992). Increased plasma FFA uptake and oxidation during prolonged exercise in trained vs. untrained humans. The American Journal of Physiology, 262(6 Pt 1), E791–E799.

    CAS  PubMed  Google Scholar 

  • Van Pelt, R. E., Gozansky, W. S., Schwartz, R. S., & Kohrt, W. M. (2003). Intravenous estrogens increase insulin clearance and action in postmenopausal women. American Journal of Physiology Endocrinology and Metabolism, 285(2), E311–E317. https://doi.org/10.1152/ajpendo.00490.2002. 00490.2002 [pii].

    Article  PubMed  PubMed Central  Google Scholar 

  • van Rooij, E., Fielitz, J., Sutherland, L. B., Thijssen, V. L., Crijns, H. J., Dimaio, M. J., Shelton, J., De Windt, L. J., Hill, J. A., & Olson, E. N. (2010). Myocyte enhancer factor 2 and class II histone deacetylases control a gender-specific pathway of cardioprotection mediated by the estrogen receptor. Circulation Research, 106(1), 155–165. doi:CIRCRESAHA.109.207084 [pii]. https://doi.org/10.1161/CIRCRESAHA.109.207084.

    Article  CAS  PubMed  Google Scholar 

  • Vasconsuelo, A., Milanesi, L., & Boland, R. (2008). 17Beta-estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: Role of the phosphatidylinositol 3-kinase/Akt pathway. The Journal of Endocrinology, 196(2), 385–397. doi:196/2/385 [pii]. https://doi.org/10.1677/JOE-07-0250.

    Article  CAS  PubMed  Google Scholar 

  • Villablanca, A., Lubahn, D., Shelby, L., Lloyd, K., & Barthold, S. (2004). Susceptibility to early atherosclerosis in male mice is mediated by estrogen receptor alpha. Arteriosclerosis, Thrombosis, and Vascular Biology, 24(6), 1055–1061. https://doi.org/10.1161/01.ATV.0000130467.65290.d4.

    Article  CAS  PubMed  Google Scholar 

  • Vogel, H., Wolf, S., Rabasa, C., Rodriguez-Pacheco, F., Babaei, C. S., Stober, F., Goldschmidt, J., DiMarchi, R. D., Finan, B., Tschop, M. H., Dickson, S. L., Schurmann, A., & Skibicka, K. P. (2016). GLP-1 and estrogen conjugate acts in the supramammillary nucleus to reduce food-reward and body weight. Neuropharmacology, 110(Pt A), 396–406. https://doi.org/10.1016/j.neuropharm.2016.07.039.

    Article  CAS  PubMed  Google Scholar 

  • Wang, F., He, Q., Sun, Y., Dai, X., & Yang, X. P. (2010). Female adult mouse cardiomyocytes are protected against oxidative stress. Hypertension, 55(5), 1172–1178. doi:HYPERTENSIONAHA.110.150839 [pii]. https://doi.org/10.1161/HYPERTENSIONAHA.110.150839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wellen, K. E., & Hotamisligil, G. S. (2005). Inflammation, stress, and diabetes. The Journal of Clinical Investigation, 115(5), 1111–1119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wiik, A., Gustafsson, T., Esbjornsson, M., Johansson, O., Ekman, M., Sundberg, C. J., & Jansson, E. (2005). Expression of oestrogen receptor alpha and beta is higher in skeletal muscle of highly endurance-trained than of moderately active men. Acta Physiologica Scandinavica, 184(2), 105–112. doi:APS1433 [pii]. https://doi.org/10.1111/j.1365-201X.2005.01433.x.

    Article  CAS  PubMed  Google Scholar 

  • Yamada, Y., Ando, F., Niino, N., Ohta, S., & Shimokata, H. (2002). Association of polymorphisms of the estrogen receptor alpha gene with bone mineral density of the femoral neck in elderly Japanese women. Journal of Molecular Medicine, 80(7), 452–460.

    Article  CAS  PubMed  Google Scholar 

  • Yang, G., Badeanlou, L., Bielawski, J., Roberts, A. J., Hannun, Y. A., & Samad, F. (2009a). Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. American Journal of Physiology. Endocrinology and Metabolism, 297(1), E211–E224. https://doi.org/10.1152/ajpendo.91014.2008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, X., Deignan, J. L., Qi, H., Zhu, J., Qian, S., Zhong, J., Torosyan, G., Majid, S., Falkard, B., Kleinhanz, R. R., Karlsson, J., Castellani, L. W., Mumick, S., Wang, K., Xie, T., Coon, M., Zhang, C., Estrada-Smith, D., Farber, C. R., Wang, S. S., van Nas, A., Ghazalpour, A., Zhang, B., Macneil, D. J., Lamb, J. R., Dipple, K. M., Reitman, M. L., Mehrabian, M., Lum, P. Y., Schadt, E. E., Lusis, A. J., & Drake, T. A. (2009b). Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nature Genetics, 41(4), 415–423. doi:ng.325 [pii]. https://doi.org/10.1038/ng.325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yki-Jarvinen, H. (1984). Sex and insulin sensitivity. Metabolism, 33(11), 1011–1015.

    Article  CAS  PubMed  Google Scholar 

  • Zorzano, A., Palacin, M., & Guma, A. (2005). Mechanisms regulating GLUT4 glucose transporter expression and glucose transport in skeletal muscle. Acta Physiologica Scandinavica, 183(1), 43–58. doi:APS1380 [pii].. https://doi.org/10.1111/j.1365-201X.2004.01380.x.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from National Institutes of Health DK89109 and DK063491, NIH Nuclear Receptor Signaling Atlas (NURSA NDSP), UCLA Department of Medicine, UCLA Iris-Cantor Women’s Health Foundation, and the UCLA Jonsson Comprehensive Cancer Center. We would like to acknowledge all of the terrific science performed on ERα by many of our esteemed colleagues; however due to page limits we are unable to cite a large number of studies. We would like to take this opportunity to thank Dr. Kenneth Korach for his generous support of our research and for providing us with the ERα floxed mouse as well as a variety of powerful molecular tools.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Andrea L. Hevener, Zhenqi Zhou, Brian G. Drew & Vicent Ribas

Authors
  1. Andrea L. Hevener
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhenqi Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brian G. Drew
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vicent Ribas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrea L. Hevener .

Editor information

Editors and Affiliations

  1. Department of Medicine, Section of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, Louisiana, USA

    Franck Mauvais-Jarvis

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Hevener, A.L., Zhou, Z., Drew, B.G., Ribas, V. (2017). The Role of Skeletal Muscle Estrogen Receptors in Metabolic Homeostasis and Insulin Sensitivity. In: Mauvais-Jarvis, F. (eds) Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity. Advances in Experimental Medicine and Biology, vol 1043. Springer, Cham. https://doi.org/10.1007/978-3-319-70178-3_13

Download citation

Publish with us

Policies and ethics

Search

Navigation