Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Hormone Molecular Biology and Clinical Investigation

Editor-in-Chief: Chetrite, Gérard S.

Editorial Board: Alexis, Michael N. / Baniahmad, Aria / Beato, Miguel / Bouillon, Roger / Brodie, Angela / Carruba, Giuseppe / Chen, Shiuan / Cidlowski, John A. / Clarke, Robert / Coelingh Bennink, Herjan J.T. / Darbre, Philippa D. / Drouin, Jacques / Dufau, Maria L. / Edwards, Dean P. / Falany, Charles N. / Fernandez-Perez, Leandro / Ferroud, Clotilde / Feve, Bruno / Flores-Morales, Amilcar / Foster, Michelle T. / Garcia-Segura, Luis M. / Gastaldelli, Amalia / Gee, Julia M.W. / Genazzani, Andrea R. / Greene, Geoffrey L. / Groner, Bernd / Hampl, Richard / Hilakivi-Clarke, Leena / Hubalek, Michael / Iwase, Hirotaka / Jordan, V. Craig / Klocker, Helmut / Kloet, Ronald / Labrie, Fernand / Mendelson, Carole R. / Mück, Alfred O. / Nicola, Alejandro F. / O'Malley, Bert W. / Raynaud, Jean-Pierre / Ruan, Xiangyan / Russo, Jose / Saad, Farid / Sanchez, Edwin R. / Schally, Andrew V. / Schillaci, Roxana / Schindler, Adolf E. / Söderqvist, Gunnar / Speirs, Valerie / Stanczyk, Frank Z. / Starka, Luboslav / Sutter, Thomas R. / Tresguerres, Jesús A. / Wahli, Walter / Wildt, Ludwig / Yang, Kaiping / Yu, Qi

4 Issues per year

CiteScore 2017: 2.48

SCImago Journal Rank (SJR) 2017: 1.021
Source Normalized Impact per Paper (SNIP) 2017: 0.830

See all formats and pricing
More options …
Volume 15, Issue 3


Implications of estrogen receptor alpha and estrogen receptor beta for adipose tissue functions and cardiometabolic complications

Hui Gao / Karin Dahlman-Wright
Published Online: 2013-08-14 | DOI: https://doi.org/10.1515/hmbci-2013-0021


There is growing evidence that estrogen signaling regulates energy metabolism and exerts important functions in maintaining adipose tissue metabolism, including controlling the distribution of body fat. Changes in the physiological functions of adipose tissue, particularly the white adipose tissue, have been strongly connected to obesity and the development of related cardiometabolic complications. In this review, we will focus on discussing the role of estrogen signaling in regulating adipocyte differentiation, metabolism and its endocrine function with a focus on the possible underlying molecular mechanisms mediated by estrogen receptor α and estrogen receptor β.

Keywords: adipose tissue; cardiometabolic complications; estrogen receptors


  • 1.

    Barros RP, Gustafsson JA. Estrogen receptors and the metabolic network. Cell Metab 2011;14:289–99.CrossrefGoogle Scholar

  • 2.

    Foryst-Ludwig A, Kintscher U. Metabolic impact of estrogen signalling through ERalpha and ERbeta. J Steroid Biochem Mol Biol 2010;122:74–81.CrossrefGoogle Scholar

  • 3.

    Vitale C, Mendelsohn ME, Rosano GM. Gender differences in the cardiovascular effect of sex hormones. Nat Rev Cardiol 2009;6:532–42.PubMedCrossrefGoogle Scholar

  • 4.

    Szmuilowicz ED, Stuenkel CA, Seely EW. Influence of menopause on diabetes and diabetes risk. Nat Rev Endocrinol 2009;5:553–8.CrossrefPubMedGoogle Scholar

  • 5.

    Cignarella A, Kratz M, Bolego C. Emerging role of estrogen in the control of cardiometabolic disease. Trends Pharmacol Sci 2010;31:183–9.PubMedCrossrefGoogle Scholar

  • 6.

    Wild SH, Byrne CD. ABC of obesity. Risk factors for diabetes and coronary heart disease. BMJ 2006;333:1009–11.CrossrefPubMedGoogle Scholar

  • 7.

    Cannon CP. Obesity-related cardiometabolic complications. Clin Cornerstone 2008;9:11–9; discussion 20–2.CrossrefGoogle Scholar

  • 8.

    Flegal KM, Kit BK, Orpana H, Graubard BI. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. J Am Med Assoc 2013;309:71–82.Google Scholar

  • 9.

    Seale P, Lazar MA. Brown fat in humans: turning up the heat on obesity. Diabetes 2009;58:1482–4.CrossrefPubMedGoogle Scholar

  • 10.

    Ravussin E, Galgani JE. The implication of brown adipose tissue for humans. Annu Rev Nutr 2011;31:33–47.CrossrefGoogle Scholar

  • 11.

    Klaus S. Adipose tissue as a regulator of energy balance. Curr Drug Targets 2004;5:241–50.CrossrefPubMedGoogle Scholar

  • 12.

    Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med (Maywood) 2004;229:1127–35.Google Scholar

  • 13.

    Pallottini V, Bulzomi P, Galluzzo P, Martini C, Marino M. Estrogen regulation of adipose tissue functions: involvement of estrogen receptor isoforms. Infect Disord Drug Targets 2008;8:52–60.CrossrefGoogle Scholar

  • 14.

    Despres JP. Abdominal obesity as important component of insulin-resistance syndrome. Nutrition 9:452–9.Google Scholar

  • 15.

    Kristensen K, Pedersen SB, Vestergaard P, Mosekilde L, Richelsen B. Hormone replacement therapy affects body composition and leptin differently in obese and non-obese postmenopausal women. J Endocrinol 1999;163:55–62.Google Scholar

  • 16.

    Bonds DE, Lasser N, Qi L, Brzyski R, Caan B, Heiss G, Limacher MC, Liu JH, Mason E, Oberman A, O’Sullivan MJ, Phillips LS, Prineas RJ, Tinker L. The effect of conjugated equine oestrogen on diabetes incidence: the Women’s Health Initiative randomised trial. Diabetologia 2006;49:459–68.CrossrefGoogle Scholar

  • 17.

    Fox CS, Heard-Costa NL, Wilson PW, Levy D, D’Agostino RB Sr., Atwood LD. Genome-wide linkage to chromosome 6 for waist circumference in the Framingham Heart Study. Diabetes 2004;53:1399–402.CrossrefGoogle Scholar

  • 18.

    Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356–9.Google Scholar

  • 19.

    Janssen I, Katzmarzyk PT, Ross R. Body mass index, waist circumference, and health risk: evidence in support of current National Institutes of Health guidelines. Arch Intern Med 2002;162:2074–9.Google Scholar

  • 20.

    Nilsson M, Dahlman I, Jiao H, Gustafsson JA, Arner P, Dahlman-Wright K. Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis – a cohort study. BMC Med Genet 2007;8:73.CrossrefGoogle Scholar

  • 21.

    Yan H, Guo Y, Yang TL, Zhao LJ, Deng HW. A family-based association study identified CYP17 as a candidate gene for obesity susceptibility in Caucasians. Genet Mol Res 2012;11:1967–74.Google Scholar

  • 22.

    Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci USA 2000;97:12729–34.CrossrefGoogle Scholar

  • 23.

    Takeda K, Toda K, Saibara T, Nakagawa M, Saika K, Onishi T, Sugiura T, Shizuta Y. Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol 2003;176:237–46.Google Scholar

  • 24.

    Fisher CR, Graves KH, Parlow AF, Simpson ER. Characterization of mice deficient in aromatase (ArKO) because of targeted disruption of the cyp19 gene. Proc Natl Acad Sci USA 1998;95:6965–70.Google Scholar

  • 25.

    Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ, Clegg DJ, Kaplitt MG, Ogawa S. Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci USA 2007;104:2501–6.CrossrefGoogle Scholar

  • 26.

    Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG, Davis KE, Zhang X, Zou F, Gent LM, Hahner LD, Khan SA, Elias CF, Elmquist JK, Clegg DJ. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 2011;14:453–65.CrossrefGoogle Scholar

  • 27.

    Brown LM, Clegg DJ. Central effects of estradiol in the regulation of food intake, body weight, and adiposity. J Steroid Biochem Mol Biol 2010;122:65–73.CrossrefGoogle Scholar

  • 28.

    Dieudonne MN, Leneveu MC, Giudicelli Y, Pecquery R. Evidence for functional estrogen receptors alpha and beta in human adipose cells: regional specificities and regulation by estrogens. Am J Physiol Cell Physiol 2004;286:C655–61.Google Scholar

  • 29.

    Gao H, Dahlman-Wright K. The gene regulatory networks controlled by estrogens. Mol Cell Endocrinol 2011;334:83–90.CrossrefGoogle Scholar

  • 30.

    Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA. Mechanisms of estrogen action. Physiol Rev 2001;81:1535–65.Google Scholar

  • 31.

    Green S, Walter P, Greene G, Krust A, Goffin C, Jensen E, Scrace G, Waterfield M, Chambon P. Cloning of the human oestrogen receptor cDNA. J Steroid Biochem 1986;24:77–83.CrossrefGoogle Scholar

  • 32.

    Enmark E, Gustafsson JA. Oestrogen receptors – an overview. J Intern Med 1999;246:133–8.Google Scholar

  • 33.

    Gronemeyer H, Laudet V. Transcription factors 3: nuclear receptors. Protein Profile 1995;2:1173–308.Google Scholar

  • 34.

    Kuiper GG, Carlsson B, Grandien K, Enmark E, Haggblad J, Nilsson S, Gustafsson JA. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 1997;138:863–70.Google Scholar

  • 35.

    Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA. International Union of Pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 2006;58:773–81.CrossrefGoogle Scholar

  • 36.

    Ignar-Trowbridge DM, Nelson KG, Bidwell MC, Curtis SW, Washburn TF, McLachlan JA, Korach KS. Coupling of dual signaling pathways: epidermal growth factor action involves the estrogen receptor. Proc Natl Acad Sci USA 1992;89:4658–62.CrossrefGoogle Scholar

  • 37.

    Curtis SW, Washburn T, Sewall C, DiAugustine R, Lindzey J, Couse JF, Korach KS. Physiological coupling of growth factor and steroid receptor signaling pathways: estrogen receptor knockout mice lack estrogen-like response to epidermal growth factor. Proc Natl Acad Sci USA 1996;93:12626–30.CrossrefGoogle Scholar

  • 38.

    Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM, Webb P. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 2000;74:311–7.Google Scholar

  • 39.

    Safe S. Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm 2001;62:231–52.Google Scholar

  • 40.

    Zhao C, Gao H, Liu Y, Papoutsi Z, Jaffrey S, Gustafsson JA, Dahlman-Wright K. Genome-wide mapping of estrogen receptor-beta-binding regions reveals extensive cross-talk with transcription factor activator protein-1. Cancer Res 2010;70:5174–83.Google Scholar

  • 41.

    Flouriot G, Brand H, Denger S, Metivier R, Kos M, Reid G, Sonntag-Buck V, Gannon F. Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J 2000;19:4688–700.Google Scholar

  • 42.

    Ogawa S, Inoue S, Watanabe T, Orimo A, Hosoi T, Ouchi Y, Muramatsu M. Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor ofestrogen action in human. Nucleic Acids Res 1998;26:3505–12.CrossrefGoogle Scholar

  • 43.

    Zhao C, Toresson G, Xu L, Koehler KF, Gustafsson JA, Dahlman-Wright K. Mouse estrogen receptor beta isoforms exhibit differences in ligand selectivity and coactivator recruitment. Biochemistry 2005;44:7936–44.CrossrefGoogle Scholar

  • 44.

    Driggers PH, Segars JH. Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth factors and phosphorylation in estrogen signaling. Trends Endocrinol Metab 2002;10:422–7.CrossrefGoogle Scholar

  • 45.

    Levin ER. Plasma membrane estrogen receptors. Trends Endocrinol Metab 2009;20:477–82.CrossrefGoogle Scholar

  • 46.

    Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science 2005;307:1625–30.Google Scholar

  • 47.

    Martensson UE, Salehi SA, Windahl S, Gomez MF, Sward K, Daszkiewicz-Nilsson J, Wendt A, Andersson N, Hellstrand P, Grande PO, Owman C, Rosen CJ, Adamo ML, Lundquist I, Rorsman P, Nilsson BO, Ohlsson C, Olde B, Leeb-Lundberg LM. Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice. Endocrinology 2009;150:687–98.Google Scholar

  • 48.

    Rodriguez-Cuenca S, Monjo M, Proenza AM, Roca P. Depot differences in steroid receptor expression in adipose tissue: possible role of the local steroid milieu. Am J Physiol Endocrinol Metab 2005;288:E200–7.Google Scholar

  • 49.

    Pedersen SB, Bruun JM, Hube F, Kristensen K, Hauner H, Richelsen B. Demonstration of estrogen receptor subtypes alpha and beta in human adipose tissue: influences of adipose cell differentiation and fat depot localization. Mol Cell Endocrinol 2001;182:27–37.Google Scholar

  • 50.

    Nilsson M, Dahlman I, Ryden M, Nordstrom EA, Gustafsson JA, Arner P, Dahlman-Wright K. Oestrogen receptor alpha gene expression levels are reduced in obese compared to normal weight females. Int J Obes (Lond) 2007;31:900–7.CrossrefGoogle Scholar

  • 51.

    Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, Dahlman-Wright K, Nilsson S, Gustafsson JA, Efendic S, Khan A. Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 2006;49:588–97.CrossrefGoogle Scholar

  • 52.

    Foryst-Ludwig A, Clemenz M, Hohmann S, Hartge M, Sprang C, Frost N, Krikov M, Bhanot S, Barros R, Morani A, Gustafsson JA, Unger T, Kintscher U. Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 2008;4:e1000108.CrossrefGoogle Scholar

  • 53.

    McInnes KJ, Andersson TC, Simonyte K, Soderstrom I, Mattsson C, Seckl JR, Olsson T. Association of 11beta-hydroxysteroid dehydrogenase type I expression and activity with estrogen receptor beta in adipose tissue from postmenopausal women. Menopause 2012;19:1347–52.Google Scholar

  • 54.

    Lundholm L, Putnik M, Otsuki M, Andersson S, Ohlsson C, Gustafsson JA, Dahlman-Wright K. Effects of estrogen on gene expression profiles in mouse hypothalamus and white adipose tissue: target genes include glutathione peroxidase 3 and cell death-inducing DNA fragmentation factor, alpha-subunit-like effector A. J Endocrinol 2008;196:547–57.Google Scholar

  • 55.

    Penza M, Montani C, Romani A, Vignolini P, Pampaloni B, Tanini A, Brandi ML, Alonso-Magdalena P, Nadal A, Ottobrini L, Parolini O, Bignotti E, Calza S, Maggi A, Grigolato PG, Di Lorenzo D. Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner. Endocrinology 2006;147:5740–51.CrossrefGoogle Scholar

  • 56.

    Lundholm L, Zang H, Hirschberg AL, Gustafsson JA, Arner P, Dahlman-Wright K. Key lipogenic gene expression can be decreased by estrogen in human adipose tissue. Fertil Steril 2008;90:44–8.CrossrefGoogle Scholar

  • 57.

    Jaubert AM, Mehebik-Mojaat N, Lacasa D, Sabourault D, Giudicelli Y, Ribiere C. Nongenomic estrogen effects on nitric oxide synthase activity in rat adipocytes. Endocrinology 2007;148:2444–52.CrossrefGoogle Scholar

  • 58.

    Stubbins RE, Holcomb VB, Hong J, Nunez NP. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr 2012;51:861–70.CrossrefGoogle Scholar

  • 59.

    Anderson LA, McTernan PG, Barnett AH, Kumar S. The effects of androgens and estrogens on preadipocyte proliferation in human adipose tissue: influence of gender and site. J Clin Endocrinol Metab 2001;86:5045–51.CrossrefGoogle Scholar

  • 60.

    Benvenuti S, Cellai I, Luciani P, Deledda C, Saccardi R, Mazzanti B, Dal Pozzo S, Serio M, Peri A. Androgens and estrogens prevent rosiglitazone-induced adipogenesis in human mesenchymal stem cells. J Endocrinol Invest 2012;35:365–71.Google Scholar

  • 61.

    Lafontan M. Advances in adipose tissue metabolism. Int J Obes (Lond) 2008;32 Suppl 7:S39–51.CrossrefGoogle Scholar

  • 62.

    Kim S, Moustaid-Moussa N. Secretory, endocrine and autocrine/paracrine function of the adipocyte. J Nutr 2000;130:3110S-5S.Google Scholar

  • 63.

    Zechner R, Zimmermann R, Eichmann TO, Kohlwein SD, Haemmerle G, Lass A, Madeo F. FAT SIGNALS–lipases and lipolysis in lipid metabolism and signaling. Cell Metab 2012;15:279–91.CrossrefGoogle Scholar

  • 64.

    Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Annu Rev Nutr 2007;27:79–101.CrossrefGoogle Scholar

  • 65.

    Carmen GY, Victor SM. Signalling mechanisms regulating lipolysis. Cell Signal 2006;18:401–8.CrossrefGoogle Scholar

  • 66.

    Palin SL, McTernan PG, Anderson LA, Sturdee DW, Barnett AH, Kumar S. 17Beta-estradiol and anti-estrogen ICI:compound 182,780 regulate expression of lipoprotein lipase and hormone-sensitive lipase in isolated subcutaneous abdominal adipocytes. Metabolism 2003;52:383–8.Google Scholar

  • 67.

    Pedersen SB, Kristensen K, Hermann PA, Katzenellenbogen JA, Richelsen B. Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. J Clin Endocrinol Metab 2004;89:1869–78.CrossrefGoogle Scholar

  • 68.

    Wend K, Wend P, Drew BG, Hevener AL, Miranda-Carboni GA, Krum SA. ERalpha regulates lipid metabolism in bone through ATGL and perilipin. J Cell Biochem 2013;114:1306–14.CrossrefGoogle Scholar

  • 69.

    Zhang H, Chen X, Sairam MR. Novel genes of visceral adiposity: identification of mouse and human mesenteric estrogen-dependent adipose (MEDA)-4 gene and its adipogenic function. Endocrinology 2012;153:2665–76.Google Scholar

  • 70.

    Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001;60:329–39.CrossrefGoogle Scholar

  • 71.

    Waki H, Tontonoz P. Endocrine functions of adipose tissue. Annu Rev Pathol 2007;2:31–56.CrossrefGoogle Scholar

  • 72.

    Karastergiou K, Smith SR, Greenberg AS, Fried SK. Sex differences in human adipose tissues – the biology of pear shape. Biol Sex Differ 2012;3:13.CrossrefGoogle Scholar

  • 73.

    Machinal F, Dieudonne MN, Leneveu MC, Pecquery R, Giudicelli Y. In vivo and in vitro ob gene expression and leptin secretion in rat adipocytes: evidence for a regional specific regulation by sex steroid hormones. Endocrinology 1999;140:1567–74.CrossrefGoogle Scholar

  • 74.

    Sowers JR. Endocrine functions of adipose tissue: focus on adiponectin. Clin Cornerstone 2008;9:32–8; discussion 9–40.CrossrefGoogle Scholar

  • 75.

    Horenburg S, Fischer-Posovszky P, Debatin KM, Wabitsch M. Influence of sex hormones on adiponectin expression in human adipocytes. Horm Metab Res 2008;40:779–86.CrossrefGoogle Scholar

  • 76.

    Gao H, Falt S, Sandelin A, Gustafsson JA, Dahlman-Wright K. Genome-wide identification of estrogen receptor alpha-binding sites in mouse liver. Mol Endocrinol 2008;22:10–22.CrossrefGoogle Scholar

About the article

Corresponding author: Karin Dahlman-Wright, Department of Biosciences and Nutrition, Karolinska Institutet, NOVUM, Hälsovägen 7, SE-141 57 Huddinge, Phone: +46 8 524 81089, +46 70 726 6541

Received: 2013-05-14

Accepted: 2013-07-17

Published Online: 2013-08-14

Published in Print: 2013-09-01

Citation Information: Hormone Molecular Biology and Clinical Investigation, Volume 15, Issue 3, Pages 81–90, ISSN (Online) 1868-1891, ISSN (Print) 1868-1883, DOI: https://doi.org/10.1515/hmbci-2013-0021.

Export Citation

©2013 by Walter de Gruyter Berlin Boston.Get Permission

Comments (0)

Please log in or register to comment.
Log in