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DOI: 10.1055/s-0030-1249639
© Georg Thieme Verlag KG Stuttgart · New York
Effects of 17β-Estradiol on Preadipocyte Proliferation in Human Adipose Tissue: Involvement of IGF1-R Signaling
Publikationsverlauf
received 27.08.2009
accepted 23.02.2010
Publikationsdatum:
08. April 2010 (online)
![](https://www.thieme-connect.de/media/hmr/201007/lookinside/thumbnails/10.1055-s-0030-1249639-1.jpg)
Abstract
Estrogens are known to stimulate the proliferation of human preadipocytes. However, the molecular mechanisms underlying the increased cell growth by these steroids are poorly understood. In the present study, we have demonstrated that the proliferative effect of 17β-estradiol involves the induction of both cell cycle gene expressions, c-myc and cyclin D1. Moreover, the mitogenic effects of 17β-estradiol are suppressed by the pure antagonist ICI 182780 suggesting that estradiol action is mediated by estrogen receptor (ER). We have also shown that 17β-estradiol is able to inhibit human preadipocyte apoptosis capacity as reflected by DNA fragmentation experiments and the mRNA expression of the pro- and antiapoptotic genes. Finally, 17β-estradiol significantly induces both mRNA and protein expression of RIGF1 in human preadipose cells via ER and thus reinforces the signaling pathway of the proliferative factor, IGF1. Taken together, these data reinforce the concept of cross-talk between IGF1- and ER-signaling pathways in preadipocytes and indicate that IGFI may be a critical regulator of estrogen-mediated preadipose growth.
Key words
human adipose tissue - estrogens - proliferation - IGF1 receptor - apoptosis
References
- 1 Bjorntorp P. Adipose tissue distribution and function. Int J Obes. 1991; 15 (S 02) 67-81
- 2 Bjorntorp P. The regulation of adipose tissue distribution in humans. Int J Obes Relat Metab Disord. 1996; 20 291-302
- 3 D’Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS. Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem. 2005; 280 35983-35991
- 4 Lundholm L, Zang H, Hirschberg AL, Gustafson JA, Arner P, Dahlman-Wright K. Key lipogenic gene expression can be decreased by estrogen in human adipose tissue. Fertil Steril. 2008; 90 44-48
- 5 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. Metab Clin Exper. 2003; 52 383-388
- 6 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 1869-1878
- 7 Roncari DA, Van RL. Promotion of human adipocyte precursor replication by 17beta-estradiol in culture. J Clin Invest. 1978; 62 503-508
- 8 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 Metabol. 2001; 86 5045-5051
- 9 Turgeon JL, Carr MC, Maki PM, Mendelsohn ME, Wise PM. Complex actions of sex steroids in adipose tissue, the cardiovascular system, and brain: Insights from basic science and clinical studies. Endocr Rev. 2006; 27 575-605
- 10 Crandall DL, Busler DE, Novak TJ, Weber RV, Kral JG. Identification of estrogen receptor beta RNA in human breast and abdominal subcutaneous adipose tissue. Biochem Biophys Res Commun. 1998; 248 523-526
- 11 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. 2004; 286 C655-C661
- 12 Benito M, Valverde AM, Lorenzo M. IGF-I: a mitogen also involved in differentiation processes in mammalian cells. Int J Bioch Cell Biol. 1996; 28 499-510
- 13 Hamelers IH, Van Schaik RF, Sussenbach JS, Steenbergh PH. 17beta-Estradiol responsiveness of MCF-7 laboratory strains is dependent on an autocrine signal activating the IGF type I receptor. Cancer cell Int. 2003; 3 10
- 14 Huynh H, Nickerson T, Pollak M, Yang X. Regulation of insulin-like growth factor I receptor expression by the pure antiestrogen ICI 182780. Clin Cancer Res. 1996; 2 2037-2042
- 15 Molloy CA, May FE, Westley BR. Insulin receptor substrate-1 expression is regulated by estrogen in the MCF-7 human breast cancer cell line. J Biol Chem. 2000; 275 12565-12571
- 16 Kahlert S, Nuedling S, van Eickels M, Vetter H, Meyer R, Grohe C. Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. J Biol Chem. 2000; 275 18447-18453
- 17 Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F. Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. EMBO J. 1996; 15 1292-1300
- 18 Song RX, McPherson RA, Adam L, Bao Y, Shupnik M, Kumar R, Santen RJ. Linkage of rapid estrogen action to MAPK activation by ERalpha-Shc association and Shc pathway activation. Mol Endocrinol. 2002; 16 116-127
- 19 Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995; 270 1491-1494
- 20 Stoica A, Saceda M, Fakhro A, Joyner M, Martin MB. Role of insulin-like growth factor-I in regulating estrogen receptor-alpha gene expression. J Cell Biochem. 2000; 76 605-614
- 21 Deslex S, Negrel R, Ailhaud G. Development of a chemically defined serum-free medium for differentiation of rat adipose precursor cells. Exp Cell Res. 1987; 168 15-30
- 22 Niesler CU, Siddle K, Prins JB. Human preadipocytes display a depot-specific susceptibility to apoptosis. Diabetes. 1998; 47 1365-1368
- 23 Fischer-Posovszky P, Tornqvist H, Debatin KM, Wabitsch M. Inhibition of death-receptor mediated apoptosis in human adipocytes by the insulin-like growth factor I (IGF-I)/IGF-I receptor autocrine circuit. Endocrinology. 2004; 145 1849-1859
- 24 Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72 248-254
- 25 Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987; 162 156-159
- 26 Machinal-Quelin F, Dieudonne MN, Leneveu MC, Pecquery R, Giudicelli Y. Proadipogenic effect of leptin on rat preadipocytes in vitro: activation of MAPK and STAT3 signaling pathways. Am J Physiol. 2002; 282 C853-C863
- 27 Gorzelniak K, Janke J, Engeli S, Sharma AM. Validation of endogenous controls for gene expression studies in human adipocytes and preadipocytes. Horm Metab Res. 2001; 33 625-627
- 28 Dieudonne MN, Pecquery R, Leneveu MC, Giudicelli Y. Opposite effects of androgens and estrogens on adipogenesis in rat preadipocytes: evidence for sex and site-related specificities and possible involvement of insulin-like growth factor 1 receptor and peroxisome proliferator-activated receptor gamma2. Endocrinology. 2000; 141 649-656
- 29 Prieto LM, Brown JW, Perez-Stable C, Fishman LM. High dose 17 beta-estradiol and the alpha-estrogen agonist PPT trigger apoptosis in human adrenal carcinoma cells but the beta-estrogen agonist DPN does not. Horm Metab Res. 2008; 40 311-314
- 30 Simpson ER, Merrill JC, Hollub AJ, Graham-Lorence S, Mendelson CR. Regulation of estrogen biosynthesis by human adipose cells. Endocr Rev. 1989; 10 136-148
- 31 Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med. 2004; 229 1127-1135
- 32 Jones ME, Thorburn AW, Britt KL, Hewitt KN, Wreford NG, Proietto J, Oz OK, Leury BJ, Robertson KM, Yao S, Simpson ER. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA. 2000; 97 12735-12740
- 33 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 12729-12734
- 34 Klotz DM, Hewitt SC, Korach KS, Diaugustine RP. Activation of a uterine insulin-like growth factor I signaling pathway by clinical and environmental estrogens: requirement of estrogen receptor-alpha. Endocrinology. 2000; 141 3430-3439
- 35 Garcia E, Lacasa D, Giudicelli Y. Estradiol stimulation of c-fos and c-jun expressions and activator protein-1 deoxyribonucleic acid binding activity in rat white adipocyte. Endocrinology. 2000; 141 2837-2846
- 36 Watters JJ, Campbell JS, Cunningham MJ, Krebs EG, Dorsa DM. Rapid membrane effects of steroids in neuroblastoma cells: effects of estrogen on mitogen activated protein kinase signalling cascade and c-fos immediate early gene transcription. Endocrinology. 1997; 138 4030-4033
- 37 Kuiper GG, Gustafsson JA. The novel estrogen receptor-beta subtype: potential role in the cell- and promoter-specific actions of estrogens and anti-estrogens. FEBS Lett. 1997; 410 87-90
- 38 Harrington WR, Sheng S, Barnett DH, Petz LN, Katzenellenbogen JA, Katzenellenbogen BS. Activities of estrogen receptor alpha- and beta-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression. Mol Cell Endocrinol. 2003; 206 13-22
- 39 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
- 40 Prall OW, Rogan EM, Musgrove EA, Watts CK, Sutherland RL. c-Myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Mol Cell Biol. 1998; 18 4499-4508
- 41 Mawson A, Lai A, Carroll JS, Sergio CM, Mitchell CJ, Sarcevic B. Estrogen and insulin/IGF-1 cooperatively stimulate cell cycle progression in MCF-7 breast cancer cells through differential regulation of c-Myc and cyclin D1. Mol Cell Endocrinol. 2005; 229 161-173
- 42 Conner P. Breast response to menopausal hormone therapy – aspects on proliferation, apoptosis and mammographic density. Ann Med. 2007; 39 28-41
- 43 Vasconsuelo A, Milanesi L, Boland R. 17Beta-estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway. J Endocrinol. 2008; 196 385-397
- 44 Falkenstein E, Tillmann HC, Christ M, Feuring M, Wehling M. Multiple actions of steroid hormones – a focus on rapid, nongenomic effects. Pharmacol Rev. 2000; 52 513-556
- 45 Lacasa D, Garcia E, Agli B, Giudicelli Y. Control of rat preadipocyte adipose conversion by ovarian status: regional specificity and possible involvement of the mitogen-activated protein kinase-dependent and c-fos signaling pathways. Endocrinology. 1997; 138 2729-2734
- 46 Lee AV, Jackson JG, Gooch JL, Hilsenbeck SG, Coronado-Heinsohn E, Osborne CK, Yee D. Enhancement of insulin-like growth factor signaling in human breast cancer: estrogen regulation of insulin receptor substrate-1 expression in vitro and in vivo. Mol Endocrinol. 1999; 13 787-796
- 47 Zhang S, Li X, Burghardt R, Smith 3rd R, Safe SH. Role of estrogen receptor (ER) alpha in insulin-like growth factor (IGF)-I-induced responses in MCF-7 breast cancer cells. J Mol Endocrinol. 2005; 35 433-447
- 48 Zhu L, Pollard JW. Estradiol-17beta regulates mouse uterine epithelial cell proliferation through insulin-like growth factor 1 signaling. Proc Natl Acad Sci USA. 2007; 104 15847-15851
- 49 Hyder SM, Stancel GM, Loose-Mitchell DS. Presence of an estradiol response region in the mouse c-fos oncogene. Steroids. 1991; 56 498-504
- 50 Uht RM, Anderson CM, Webb P, Kushner PJ. Transcriptional activities of estrogen and glucocorticoid receptors are functionally integrated at the AP-1 response element. Endocrinology. 1997; 138 2900-2908
- 51 Duan R, Porter W, Safe S. Estrogen-induced c-fos protooncogene expression in MCF-7 human breast cancer cells: role of estrogen receptor Sp1 complex formation. Endocrinology. 1998; 139 1981-1990
- 52 Scheidegger KJ, Cenni B, Picard D, Delafontaine P. Estradiol decreases IGF-1 and IGF-1 receptor expression in rat aortic smooth muscle cells. Mechanisms for its atheroprotective effects. J Biol Chem. 2000; 275 38921-38928
- 53 Gagnon A, Dods P, Roustan-Delatour N, Chen CS, Sorisky A. Phosphatidylinositol-3,4,5-trisphosphate is required for insulin-like growth factor 1-mediated survival of 3T3-L1 preadipocytes. Endocrinology. 2001; 142 205-212
- 54 Bernard L, Legay C, Adriaenssens E, Mougel A, Ricort JM. Estradiol regulates the insulin-like growth factor-I (IGF-I) signalling pathway: a crucial role of phosphatidylinositol 3-kinase (PI 3-kinase) in estrogens requirement for growth of MCF-7 human breast carcinoma cells. Biochem Biophys Res Commun. 2006; 350 916-921
- 55 Daws MR, Westley BR, May FE. Paradoxical effects of overexpression of the type I insulin-like growth factor (IGF) receptor on the responsiveness of human breast cancer cells to IGFs and estradiol. Endocrinology. 1996; 137 1177-1186
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