Skip to main content
SpringerLink
Log in

2-methoxyestradiol, an endogenous metabolite of 17b-estradiol, inhibits adipocyte proliferation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The effects of 2-methoxyestradiol (2ME), a naturally occurring mammalian metabolite of 17 β-estradiol, on adipocyte growth has been investigated in mouse brown adipose tissue precursor cells developed in primary culture. 2ME inhibits brown adipocyte proliferation in a dose-response manner (IC50 = 1.7 × 10-6 M for DNA synthesis), with much higher potency than its hormone precursor 17β-estradiol, and cells acquire the typical differentiated morphology - more round with a higher content of triglycerides. 2ME causes similar effects in the immortal brown adipocyte tumor-derived hibernoma cell line HIB 1B and the immortal 3T3-F442A white adipocyte line. These findings suggest a possible role for 2ME in adipocyte proliferation, and probably in the differentiation process, entering the cells in the adipogenic program.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Susulic VS, Lowell BB: Brown adipose tissue and the regulation of body fat stores. Curr Opin Endocrinol Diabetes 3: 44–50, 1996

    Google Scholar 

  2. Rehnmark S, Nedergaard J: DNA synthesis in brown adipose tissue is under ????????‐adrenergic control. Exp Cell Res 180: 574–579, 1989

    Google Scholar 

  3. Puigserver P, Lladó I, Palou A, Gianotti M: Evidence for masking of brown adipose tissue mitochondrial GDP‐binding sites in response to fasting in rats made obese by dietary manipulation. Biochem J 279: 575–579, 1991

    Google Scholar 

  4. Moreno M, Puigserver P, Llull J, Gianotti M, Lanni A, Goglia F, Palou A: Cold exposure induces different uncoupling‐protein thermogenin masking/unmasking processes in brown adipose tissue depending on mitochondrial subtypes. Biochem J 300: 463–468, 1994

    Google Scholar 

  5. Himms‐Hagen J: Brown adipose tissue thermogenesis: Role in thermoregulation, energy regulation and obesity. In: E Schonbaum, P Lomax (eds). Thermoregulation‐Physiology & Biochemistry. Pergamon, New York, 1990, pp 327–414

    Google Scholar 

  6. Himms‐Hagen J: Brown adipose tissue thermogenesis: Interdisciplinary studies. FASEB J 4: 2890–2898, 1990

    Google Scholar 

  7. Zhao J, Unelius L, Bengtsson T, Cannon B, Nedergaard J: Coexisting ????????‐adrenoreceptor subtypes: Significance for the thermogenic process in brown‐fat cells. Am J Physiol 267: C969–C979, 1994

    Google Scholar 

  8. Puigserver P, Picó C, Stock MJ, Palou A: Effect of selective ????????‐adrenoceptor stimulation on UCP synthesis in primary cultures of brown adipocytes Mol Cell Endocrinol 117: 7–16, 1996

    Google Scholar 

  9. Cassard‐Doulcier AM, Larose M, Matamala JC, Champigny O, Bouillaud F, Ricquier D: In vitro interactions between nuclear proteins and uncoupling protein gene promoter reveal several putative transactivating factors including Ets1, retinoic X receptor, thyroid hormone receptor, and a CACCC box‐binding protein. J Biol Chem 269: 24342–24342, 1994

    Google Scholar 

  10. Alvarez R, Andrés J, Yubero P, Viñas O, Mampel T, Iglesias R, Giralt M, Villarroya F: A novel regulatory pathway of brown fat thermogenesis. Retinoic acid is a transcriptional activator of the mitochondrial uncoupling protein gene. J Biol Chem 270: 5666–5673, 1995

    Google Scholar 

  11. Puigserver P, Vázquez F, Bonet ML, Picó C, Palou A: In vitro and in vivo induction of the brown adipocyte uncoupling protein thermogenin by retinoic acid. Biochem J 317: 827–833, 1996

    Google Scholar 

  12. Klaus S, Cassard‐Doulcier AM, Ricquier D: Development of Phodopus Sungorus brown adipocytes in primary cell culture: Effect of an atypical beta‐agonist, insulin and triiodothyronine on differentiation, mitochondrial development, and expression of the uncoupling protein UCP. J Cell Biol 115: 1783–1790, 1991

    Google Scholar 

  13. Bianco AC, Sheng X, Silva JE: Adenosine 3??????????????????????,5??????????????????????‐monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes. J Biol Chem 263: 18168–18175, 1988

    Google Scholar 

  14. Silva JE: Full expression of uncoupling protein gene requires the concurrence of norepinephrine and triiodothyronine. Mol Endocrinol 2: 706–713, 1988

    Google Scholar 

  15. Nava MP, Fernández A, Abelenda M, Puerta M: Dissociation between brown adipose tissue thermogenesis and sympathetic activity in rats with high plasma levels of oestradiol. Pflügers Arch 426: 40–43, 1994

    Google Scholar 

  16. Smas CM, Sul HS: Control of adipocyte differentiation. Biochem J 309: 697–710, 1995

    Google Scholar 

  17. Ailhaud G: Adipose cell differentiation in culture. Mol Cell Biochem 49: 17–31, 1982

    Google Scholar 

  18. Casteilla L, Nogues J, Reyne Y, Riquier D: Differentiation of ovine brown adipocyte precursor cells in a chemically defined serum‐free medium. Eur J Biochem 198: 195–199, 1991

    Google Scholar 

  19. Barone S, Partek D, Bennett L, Stitzel RE, Head RJ: The influence of oestrogen and oestrogen metabolites on the sensitivity of the isolated rabbit aorta to catecholamines. Arch Pharmacol 335: 513–520, 1987

    Google Scholar 

  20. Crum R, Szabo S, Folkman J: A new class of steroids inhibits angiogenesis in the presence of heparin or a heparin fragment. Science 230: 1375–1378, 1985

    Google Scholar 

  21. Fotsis T, Zhang Y, Pepper MS, Adlercreutz H, Montesano R, Nawroth PP, Schwelgerer L: The endogenous oestrogen 2‐methoxyoestradiol inhibits angiogenesis and suppresses tumour growth. Nature (London) 368: 237–239, 1994

    Google Scholar 

  22. Klauber N, Parangi S, Flynn E, Hamel E, D'Amato RJ: Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2‐methoxyoestradiol and taxol. Cancer Res 57: 81–86, 1997

    Google Scholar 

  23. D'Amato RJ, Lin CM, Flynn E, Folkman J, Harnel E: 2‐Methoxyestradiol, an endogenous mammalian metabolite, inhibits tubulin polymerization by interacting at the colchicine site. Proc Natl Acad Sci USA 91: 3964–3968, 1994

    Google Scholar 

  24. Rehnmark S, Kopecky J, Jacobsson A, Néchad M, Herron D, Nelson BD, Obregón MJ, Nedergaard J, Cannon B: Brown adipocytes differentiated in vitro can express the gene for the uncoupling protein thermogenin. Effects of hypothyroidism and norepinephrine. Exp Cell Res 182: 75–83, 1989

    Google Scholar 

  25. Puigserver P, Herron D, Gianotti M, Palou A, Cannon B, Nedergaard J: Induction and degradation of the uncoupling protein thermogenin in brown adipocytes in vitro and in vivo. Biochem J 284: 393–398, 1992

    Google Scholar 

  26. Bradford MM: A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein‐dye binding. Anal Biochem 72: 248–254, 1976

    Google Scholar 

  27. Gelbke HP, Knuppen R: The excretion of five different 2‐hydroxyoestrogen monomethyl ethers in human pregnancy urine. J Steroid Biochem 7: 457–463, 1976

    Google Scholar 

  28. Ross SR, Choy L, Graves R A, Fox N, Solevjena V, Klaus S, Ricquier D, Spiegelman BM: Hibernoma formation in transgenic mice and isolation of a brown adipocyte cell line expressing the uncoupling protein gene. Proc Natl Acad Sci USA 89: 7561–7565, 1992

    Google Scholar 

  29. Spiegelman BM, Choy L, Hotamisligil GS, Graves RA, Tontonoz P: Regulation of adipocyte gene expression in differentiation and syndromes of obesity/diabetes. J Biol Chem 268: 6823–6826, 1993

    Google Scholar 

  30. Cushman M, He HM, Katzenellenbogen JA, Lin CM, Hamel E: Synthesis, antitubulin and antimitotic activity, and cytotoxicity of analogs of 2‐methoxyestradiol, an endogenous mammalian metabolite of estradiol that inhibits tubulin polymerization by binding to the colchicine site. J Med Chem 38: 2041–2049, 1995

    Google Scholar 

  31. Sternlicht H, Ringel I: Colchicine inhibition of microtubule assembly via copolymer formation. J Biol Chem 254: 10540–10548, 1979

    Google Scholar 

  32. Attalla H, Makela TP, Adlercreutz H, Andersson LC: 2‐Methoxyestradiol arrests cells in mitosis without depolymerizing tubulin. Biochem Biophys Res Commun 228: 467–473, 1996

    Google Scholar 

  33. Néchad M, Kuusela P, Carneheim C, Björntorp P, Nedergaard J, Cannon B: Development of brown fat cells in monolayer culture. I. Morphological and biochemical distinction from white fat cells in culture. Exp Cell Res 149: 105–118, 1983

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratori de Biologia Molecular, Nutrició i Biotecnologia, Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les Illes Balears, Palma de Mallorca, Spain

    Catalina Picó, Pere Puigserver, Paula Oliver & Andreu Palou

Authors
  1. Catalina Picó
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pere Puigserver
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paula Oliver
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreu Palou
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Picó, C., Puigserver, P., Oliver, P. et al. 2-methoxyestradiol, an endogenous metabolite of 17b-estradiol, inhibits adipocyte proliferation. Mol Cell Biochem 189, 1–7 (1998). https://doi.org/10.1023/A:1006835124149

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006835124149

Search

Navigation