Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Dual effects of sodium tungstate on adipocyte biology: inhibition of adipogenesis and stimulation of cellular oxygen consumption

International Journal of Obesity volume 33, pages 534–540 (2009)Cite this article

Abstract

Objective:

We have recently shown the in vivo anti-obesity effects of sodium tungstate. In this study, we investigate the in vitro effects of sodium tungstate on adipocyte differentiation and function.

Methods:

3T3-F442A cells were allowed to differentiate in the presence of sodium tungstate, and were analyzed for triglyceride (TG) accumulation, adipocyte differentiation and mitochondrial oxygen consumption.

Results:

Sodium tungstate treatment of adipose cells decreased TG accumulation and adipocyte differentiation. Expression of key genes for adipocyte function (aP2, ACC, fatty acid synthase (FAS) and lipoprotein lipase (LPL)) and differentiation (CCAAT enhancer-binding protein (C/EBP)α and peroxisome proliferator-activated receptor gamma (PPARγ)) was reduced by sodium tungstate, whereas C/EBPβ isoform LIP expression level was increased. TG accumulation and changes in C/EBPβ expression were partially recovered by inactivating the erk1/2 pathway. Finally, tungstate treatment increased the oxygen consumption of adipose cells without changes in the expression of oxidative genes.

Conclusions:

Sodium tungstate inhibits adipocyte differentiation by promoting the translation of LIP, a master dominant-negative regulator of this process, and regulates the mitochondrial oxygen consumption of adipose cells. These effects contribute to the anti-obesity activity of sodium tungstate and confirm its potential as a powerful alternative for the treatment of obesity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. James WP . The epidemiology of obesity: the size of the problem. J Intern Med 2008; 263: 336–352.

    Article  CAS  Google Scholar 

  2. Claret M, Corominola H, Canals I, Saura J, Barcelo-Batllori S, Guinovart JJ et al. Tungstate decreases weight gain and adiposity in obese rats through increased thermogenesis and lipid oxidation. Endocrinology 2005; 146: 4362–4369.

    Article  CAS  Google Scholar 

  3. Barbera A, Gomis RR, Prats N, Rodriguez-Gil JE, Domingo M, Gomis R et al. Tungstate is an effective antidiabetic agent in streptozotocin-induced diabetic rats: a long-term study. Diabetologia 2001; 44: 507–513.

    Article  CAS  Google Scholar 

  4. Munoz MC, Barbera A, Dominguez J, Fernandez-Alvarez J, Gomis R, Guinovart JJ . Effects of tungstate, a new potential oral antidiabetic agent, in Zucker diabetic fatty rats. Diabetes 2001; 50: 131–138.

    Article  CAS  Google Scholar 

  5. Fernandez-Alvarez J, Barbera A, Nadal B, Barcelo-Batllori S, Piquer S, Claret M et al. Stable and functional regeneration of pancreatic beta-cell population in nSTZ-rats treated with tungstate. Diabetologia 2004; 47: 470–477.

    Article  CAS  Google Scholar 

  6. Barcelo-Batllori S, Corominola H, Claret M, Canals I, Guinovart J, Gomis R . Target identification of the novel antiobesity agent tungstate in adipose tissue from obese rats. Proteomics 2005; 5: 4927–4935.

    Article  CAS  Google Scholar 

  7. Barcelo-Batllori S, Kalko SG, Esteban Y, Moreno S, Carmona MC, Gomis R . Integration of DIGE and bioinformatics analyses reveals a role of the antiobesity agent tungstate in redox and energy homeostasis pathways in brown adipose tissue. Mol Cell Proteomics 2008; 7: 378–393.

    Article  CAS  Google Scholar 

  8. Feve B . Adipogenesis: cellular and molecular aspects. Best Pract Res Clin Endocrinol Metab 2005; 19: 483–499.

    Article  CAS  Google Scholar 

  9. Farmer SR . Transcriptional control of adipocyte formation. Cell Metab 2006; 4: 263–273.

    Article  CAS  Google Scholar 

  10. Farmer SR . Regulation of PPARgamma activity during adipogenesis. Int J Obes (Lond) 2005; 29 (Suppl 1): S13–S16.

    Article  CAS  Google Scholar 

  11. Descombes P, Schibler U . A liver-enriched transcriptional activator protein, LAP, and a transcriptional inhibitory protein, LIP, are translated from the same mRNA. Cell 1991; 67: 569–579.

    Article  CAS  Google Scholar 

  12. Timchenko NA, Welm AL, Lu X, Timchenko LT . CUG repeat binding protein (CUGBP1) interacts with the 5′ region of C/EBPbeta mRNA and regulates translation of C/EBPbeta isoforms. Nucleic Acids Res 1999; 27: 4517–4525.

    Article  CAS  Google Scholar 

  13. Baldwin BR, Timchenko NA, Zahnow CA . Epidermal growth factor receptor stimulation activates the RNA binding protein CUG-BP1 and increases expression of C/EBPbeta-LIP in mammary epithelial cells. Mol Cell Biol 2004; 24: 3682–3691.

    Article  CAS  Google Scholar 

  14. Wilson-Fritch L, Burkart A, Bell G, Mendelson K, Leszyk J, Nicoloro S et al. Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone. Mol Cell Biol 2003; 23: 1085–1094.

    Article  CAS  Google Scholar 

  15. Choo HJ, Kim JH, Kwon OB, Lee CS, Mun JY, Han SS et al. Mitochondria are impaired in the adipocytes of type 2 diabetic mice. Diabetologia 2006; 49: 784–791.

    Article  CAS  Google Scholar 

  16. Vankoningsloo S, Piens M, Lecocq C, Gilson A, De Pauw A, Renard P et al. Mitochondrial dysfunction induces triglyceride accumulation in 3T3-L1 cells: role of fatty acid beta-oxidation and glucose. J Lipid Res 2005; 46: 1133–1149.

    Article  CAS  Google Scholar 

  17. Carmona MC, Louche K, Lefebvre B, Pilon A, Hennuyer N, Audinot-Bouchez V et al. S 26948: a new specific peroxisome proliferator activated receptor gamma modulator with potent antidiabetes and antiatherogenic effects. Diabetes 2007; 56: 2797–2808.

    Article  CAS  Google Scholar 

  18. Hutter E, Renner K, Pfister G, Stockl P, Jansen-Durr P, Gnaiger E . Senescence-associated changes in respiration and oxidative phosphorylation in primary human fibroblasts. Biochem J 2004; 380 (Pt 3): 919–928.

    Article  CAS  Google Scholar 

  19. Koo DH, Kim M, Chang S . WO3 nanoparticles on MCM-48 as a highly selective and versatile heterogeneous catalyst for the oxidation of olefins, sulfides, and cyclic ketones. Org Lett 2005; 7: 5015–5018.

    Article  CAS  Google Scholar 

  20. Choudary BM, Bharathi B, Reddy CV, Kantam ML, Raghavan KV . The first example of catalytic N-oxidation of tertiary amines by tungstate-exchanged Mg-Al layered double hydroxide in water: a green protocol. Chem Commun (Camb) 2001; 18: 1736–1737.

    Article  Google Scholar 

  21. Andreesen JR, Makdessi K . Tungsten, the surprisingly positively acting heavy metal element for prokaryotes. Ann N Y Acad Sci 2008; 1125: 215–229.

    Article  CAS  Google Scholar 

  22. Brondino CD, Romao MJ, Moura I, Moura JJ . Molybdenum and tungsten enzymes: the xanthine oxidase family. Curr Opin Chem Biol 2006; 10: 109–114.

    Article  CAS  Google Scholar 

  23. Moura JJ, Brondino CD, Trincao J, Romao MJ . Mo and W bis-MGD enzymes: nitrate reductases and formate dehydrogenases. J Biol Inorg Chem 2004; 9: 791–799.

    Article  CAS  Google Scholar 

  24. Deeks ED, Keam SJ . Rosiglitazone : a review of its use in type 2 diabetes mellitus. Drugs 2007; 67: 2747–2779.

    Article  CAS  Google Scholar 

  25. Massi-Benedetti M, Orsini-Federici M . Treatment of type 2 diabetes with combined therapy: what are the pros and cons? Diabetes Care 2008; 31 (Suppl 2): S131–S135.

    Article  Google Scholar 

  26. Barbera A, Rodriguez-Gil JE, Guinovart JJ . Insulin-like actions of tungstate in diabetic rats. Normalization of hepatic glucose metabolism. J Biol Chem 1994; 269: 20047–20053.

    CAS  PubMed  Google Scholar 

  27. Timchenko NA, Wang GL, Timchenko LT . RNA CUG-binding protein 1 increases translation of 20-kDa isoform of CCAAT/enhancer-binding protein beta by interacting with the alpha and beta subunits of eukaryotic initiation translation factor 2. J Biol Chem 2005; 280: 20549–20557.

    Article  CAS  Google Scholar 

  28. Welm AL, Mackey SL, Timchenko LT, Darlington GJ, Timchenko NA . Translational induction of liver-enriched transcriptional inhibitory protein during acute phase response leads to repression of CCAAT/enhancer binding protein alpha mRNA. J Biol Chem 2000; 275: 27406–27413.

    CAS  PubMed  Google Scholar 

  29. Karagiannides I, Thomou T, Tchkonia T, Pirtskhalava T, Kypreos KE, Cartwright A et al. Increased CUG triplet repeat-binding protein-1 predisposes to impaired adipogenesis with aging. J Biol Chem 2006; 281: 23025–23033.

    Article  CAS  Google Scholar 

  30. Dudaronek JM, Barber SA, Clements JE . CUGBP1 is required for IFNbeta-mediated induction of dominant-negative CEBPbeta and suppression of SIV replication in macrophages. J Immunol 2007; 179: 7262–7269.

    Article  CAS  Google Scholar 

  31. Piquer S, Barcelo-Batllori S, Julia M, Marzo N, Nadal B, Guinovart JJ et al. Phosphorylation events implicating p38 and PI3K mediate tungstate-effects in MIN6 beta cells. Biochem Biophys Res Commun 2007; 358: 385–391.

    Article  CAS  Google Scholar 

  32. Alonso M, Melani M, Converso D, Jaitovich A, Paz C, Carreras MC et al. Mitochondrial extracellular signal-regulated kinases 1/2 (ERK1/2) are modulated during brain development. J Neurochem 2004; 89: 248–256.

    Article  CAS  Google Scholar 

  33. Bijur GN, Jope RS . Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem 2003; 87: 1427–1435.

    Article  CAS  Google Scholar 

  34. Chaudhry A, Zhang C, Granneman JG . Characterization of RII(beta) and D-AKAP1 in differentiated adipocytes. Am J Physiol Cell Physiol 2002; 282: C205–C212.

    Article  CAS  Google Scholar 

  35. Livigni A, Scorziello A, Agnese S, Adornetto A, Carlucci A, Garbi C et al. Mitochondrial AKAP121 links cAMP and src signaling to oxidative metabolism. Mol Biol Cell 2006; 17: 263–271.

    Article  CAS  Google Scholar 

  36. Augereau O, Claverol S, Boudes N, Basurko MJ, Bonneu M, Rossignol R et al. Identification of tyrosine-phosphorylated proteins of the mitochondrial oxidative phosphorylation machinery. Cell Mol Life Sci 2005; 62: 1478–1488.

    Article  CAS  Google Scholar 

  37. Bender E, Kadenbach B . The allosteric ATP-inhibition of cytochrome c oxidase activity is reversibly switched on by cAMP-dependent phosphorylation. FEBS Lett 2000; 466: 130–134.

    Article  CAS  Google Scholar 

  38. Hojlund K, Wrzesinski K, Larsen PM, Fey SJ, Roepstorff P, Handberg A et al. Proteome analysis reveals phosphorylation of ATP synthase beta-subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes. J Biol Chem 2003; 278: 10436–10442.

    Article  CAS  Google Scholar 

  39. Lee I, Salomon AR, Ficarro S, Mathes I, Lottspeich F, Grossman LI et al. cAMP-dependent tyrosine phosphorylation of subunit I inhibits cytochrome c oxidase activity. J Biol Chem 2005; 280: 6094–6100.

    Article  CAS  Google Scholar 

  40. Schulenberg B, Aggeler R, Beechem JM, Capaldi RA, Patton WF . Analysis of steady-state protein phosphorylation in mitochondria using a novel fluorescent phosphosensor dye. J Biol Chem 2003; 278: 27251–27255.

    Article  CAS  Google Scholar 

  41. Steenaart NA, Shore GC . Mitochondrial cytochrome c oxidase subunit IV is phosphorylated by an endogenous kinase. FEBS Lett 1997; 415: 294–298.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The CIBER de Diabetes y Enfermedades Metabólicas Asociadas is an ISCIII project. This work was supported by the ISCIII projects CP07/00152, PI04/2553, and by the MEC project SAF 2006-07582.

Author information

Authors and Affiliations

  1. Laboratori de Diabetis i Obesitat, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, Universitat de Barcelona, Barcelona, Spain

    M C Carmona, M Amigó, S Barceló-Batllori, M Julià, Y Esteban, S Moreno & R Gomis

  2. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain

    M C Carmona, M Amigó, S Barceló-Batllori, M Julià, Y Esteban, S Moreno & R Gomis

Authors
  1. M C Carmona
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Amigó
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Barceló-Batllori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Julià
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Esteban
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R Gomis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M C Carmona.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carmona, M., Amigó, M., Barceló-Batllori, S. et al. Dual effects of sodium tungstate on adipocyte biology: inhibition of adipogenesis and stimulation of cellular oxygen consumption. Int J Obes 33, 534–540 (2009). https://doi.org/10.1038/ijo.2009.34

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2009.34

Keywords

This article is cited by

Search

Advanced search

Quick links