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:

Adipocyte-derived products induce the transcription of the StAR promoter and stimulate aldosterone and cortisol secretion from adrenocortical cells through the Wnt-signaling pathway

International Journal of Obesity volume 31, pages 864–870 (2007)Cite this article

Abstract

Context:

Obesity is associated with hypersecretion of cortisol and aldosterone and a high prevalence of arterial hypertension. At the cellular level, a direct effect of adipocytes on the expression of the steroidogenic acute regulatory (StAR) protein, a regulator of cortisol and aldosterone synthesis, and on aldosterone and cortisol secretion has been shown. However, the molecular mechanisms mediating this effect are not known.

Objective:

Wnt-signaling molecules are secreted by adipocytes and regulate the activity of SF-1, a key transcription factor in adrenal steroidogenesis. Therefore, we investigated whether adipocytes stimulate adrenal steroidogenesis through the activation of Wnt-signaling.

Results:

Using immunohistochemistry, we detected the expression of frizzled and β-catenin in the adult human adrenal cortex. Transient transfection of a Wnt-dependent reporter-gene into adrenal NCI-H295R cells showed an induction of Wnt-mediated transcription to 308% after treatment with human fat cell-conditioned medium (FCCM). This finding was paralleled by an induction of StAR promoter activity (420%) by FCCM. The induction of StAR promoter activity by FCCM was inhibited by 49% when Wnt-signaling was blocked by the soluble Wnt-antagonist secreted Frizzled-Related-Protein-1 (sFRP-1). Overexpression of a constitutively active mutant of β-catenin induced the transcription of the StAR promoter (440%). β-Catenin and FCCM induced SF-1-mediated transcription at a SF-1-driven reporter gene (420 and 402%, respectively). Furthermore, the secretion of aldosterone and cortisol by NCI-H295R cells induced by FCCM was significantly inhibited by the Wnt-antagonist sFRP-1.

Conclusion:

These data indicate that the Wnt-signaling pathway is one of the mechanisms mediating the effects of fat cells on adrenal StAR transcription and aldosterone and cortisol secretion.

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
Figure 5

Similar content being viewed by others

References

  1. Dalton M, Cameron AJ, Zimmet PZ, Shaw JE, Jolley D, Dunstan DW et al. Waist circumference, waist-hip ratio and body mass index and their correlation with cardiovascular disease risk factors in Australian adults. J Intern Med 2003; 254: 555–563.

    Article  CAS  Google Scholar 

  2. Goodfriend TL, Egan BM, Kelley DE . Aldosterone in obesity. Endocr Res 1998; 24: 789–796.

    Article  CAS  Google Scholar 

  3. Goodfriend TL, Kelley DE, Goodpaster BH, Winters SJ . Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Obes Res 1999; 7: 355–362.

    Article  CAS  Google Scholar 

  4. Goodfriend TL, Egan BM, Kelley DE . Plasma aldosterone, plasma lipoproteins, obesity and insulin resistance in humans. Prostaglandins Leukot Essent Fatty Acids 1999; 60: 401–405.

    Article  CAS  Google Scholar 

  5. Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V et al. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med 1989; 321: 580–585.

    Article  CAS  Google Scholar 

  6. Lamounier-Zepter V, Bornstein SR, Ehrhart-Bornstein M . Mechanisms of obesity-related hypertension. Hormone Metab Res 2004; 36: 376–380.

    Article  CAS  Google Scholar 

  7. Kelly JJ, Mangos G, Williamson PM, Whitworth JA . Cortisol and hypertension. Clin Exp Pharmacol Physiol Suppl 1998; 25: S51–S56.

    Article  CAS  Google Scholar 

  8. Yanovski JA, Yanovski SZ, Gold PW, Chrousos GP . Differences in corticotropin-releasing hormone-stimulated adrenocorticotropin and cortisol before and after weight loss. J Clin Endocrinol Metab 1997; 82: 1874–1878.

    Article  CAS  Google Scholar 

  9. de Paula RB, da Silva AA, Hall JE . Aldosterone antagonism attenuates obesity-induced hypertension and glomerular hyperfiltration. Hypertension 2004; 43: 41–47.

    Article  CAS  Google Scholar 

  10. Ehrhart-Bornstein M, Lamounier-Zepter V, Schraven A, Langenbach J, Willenberg HS, Barthel A et al. Human adipocytes secrete mineralocorticoid-releasing factors. Proc Natl Acad Sci USA 2003; 100: 14211–14216.

    Article  CAS  Google Scholar 

  11. Bays H, Mandarino L, DeFronzo RA . Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004; 89: 463–478.

    Article  CAS  Google Scholar 

  12. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL et al. Inhibition of adipogenesis by Wnt signaling. Science 2000; 289: 950–953.

    Article  CAS  Google Scholar 

  13. Longo KA, Kennell JA, Ochocinska MJ, Ross SE, Wright WS, MacDougald OA . Wnt signaling protects 3T3-L1 preadipocytes from apoptosis through induction of insulin-like growth factors. J Biol Chem 2002; 277: 38239–38244.

    Article  CAS  Google Scholar 

  14. Logan CY, Nusse R . The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 2004; 20: 781–810.

    Article  CAS  Google Scholar 

  15. Gummow BM, Winnay JN, Hammer GD . Convergence of Wnt signaling and steroidogenic factor-1 (SF-1) on transcription of the rat inhibin alpha gene. J Biol Chem 2003; 278: 26572–26579.

    Article  CAS  Google Scholar 

  16. Hossain A, Saunders GF . Synergistic cooperation between the beta-catenin signaling pathway and steroidogenic factor 1 in the activation of the Mullerian inhibiting substance type II receptor. J Biol Chem 2003; 278: 26511–26516.

    Article  CAS  Google Scholar 

  17. Jordan BK, Shen JH, Olaso R, Ingraham HA, Vilain E . Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing steroidogenic factor 1/beta-catenin synergy. Proc Natl Acad Sci USA 2003; 100: 10866–10871.

    Article  CAS  Google Scholar 

  18. Val P, Lefrancois-Martinez AM, Veyssiere G, Martinez A . SF-1 a key player in the development and differentiation of steroidogenic tissues. Nucl Recept 2003; 1: 8.

    Article  Google Scholar 

  19. Stocco DM, Wang X, Jo Y, Manna PR . Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol 2005; 19: 2647–2659.

    Article  CAS  Google Scholar 

  20. Hagen T, Sethi JK, Foxwell N, Vidal-Puig A . Signalling activity of beta-catenin targeted to different subcellular compartments. Biochem J 2004; 379 (Part 2): 471–477.

    Article  CAS  Google Scholar 

  21. Lala DS, Syka PM, Lazarchik SB, Mangelsdorf DJ, Parker KL, Heyman RA . Activation of the orphan nuclear receptor steroidogenic factor 1 by oxysterols. Proc Natl Acad Sci USA 1997; 94: 4895–4900.

    Article  CAS  Google Scholar 

  22. Caron KM, Ikeda Y, Soo SC, Stocco DM, Parker KL, Clark BJ . Characterization of the promoter region of the mouse gene encoding the steroidogenic acute regulatory protein. Mol Endocrinol 1997; 11: 138–147.

    Article  CAS  Google Scholar 

  23. Rainey WE, Bird IM, Mason JI . The NCI-H295 cell line: a pluripotent model for human adrenocortical studies. Mol Cell Endocrinol 1994; 100: 45–50.

    Article  CAS  Google Scholar 

  24. Gazdar AF, Oie HK, Shackleton CH, Chen TR, Triche TJ, Myers CE et al. Establishment and characterization of a human adrenocortical carcinoma cell line that expresses multiple pathways of steroid biosynthesis. Cancer Res 1990; 50: 5488–5496.

    CAS  PubMed  Google Scholar 

  25. Schinner S, Barthel A, Dellas C, Grzeskowiak R, Sharma SK, Oetjen E et al. Protein kinase B activity is sufficient to mimic the effect of insulin on glucagon gene transcription. J Biol Chem 2005; 280: 7369–7376.

    Article  CAS  Google Scholar 

  26. Suwa T, Chen M, Hawks CL, Hornsby PJ . Zonal expression of dickkopf-3 and components of the Wnt signalling pathways in the human adrenal cortex. J Endocrinol 2003; 178: 149–158.

    Article  CAS  Google Scholar 

  27. Eckel RH, Grundy SM, Zimmet PZ . The metabolic syndrome. Lancet 2005; 365: 1415–1428.

    Article  CAS  Google Scholar 

  28. Kopelman PG . Obesity as a medical problem. Nature 2000; 404: 635–643.

    Article  CAS  Google Scholar 

  29. Egan BM, Stepniakowski K, Goodfriend TL . Renin and aldosterone are higher and the hyperinsulinemic effect of salt restriction greater in subjects with risk factors clustering. Am J Hypertens 1994; 7 (10 Part 1): 886–893.

    Article  CAS  Google Scholar 

  30. Licata G, Scaglione R, Ganguzza A, Corrao S, Donatelli M, Parrinello G et al. Central obesity and hypertension. Relationship between fasting serum insulin, plasma renin activity, and diastolic blood pressure in young obese subjects. Am J Hypertens 1994; 7 (4 Part 1): 314–320.

    Article  CAS  Google Scholar 

  31. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM . Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372: 425–432.

    Article  CAS  Google Scholar 

  32. Kahn BB, Flier JS . Obesity and insulin resistance. J Clin Invest 2000; 106: 473–481.

    Article  CAS  Google Scholar 

  33. Hammer GD, Parker KL, Schimmer BP . Minireview: transcriptional regulation of adrenocortical development. Endocrinology 2005; 146: 1018–1024.

    Article  CAS  Google Scholar 

  34. Heikkila M, Peltoketo H, Leppaluoto J, Ilves M, Vuolteenaho O, Vainio S . Wnt-4 deficiency alters mouse adrenal cortex function, reducing aldosterone production. Endocrinology 2002; 143: 4358–4365.

    Article  CAS  Google Scholar 

  35. Fujino T, Asaba H, Kang MJ, Ikeda Y, Sone H, Takada S et al. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci USA 2003; 100: 229–234.

    Article  CAS  Google Scholar 

  36. Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med 2003; 349: 2483–2494.

    Article  CAS  Google Scholar 

  37. Berndt T, Craig TA, Bowe AE, Vassiliadis J, Reczek D, Finnegan R et al. Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent. J Clin Invest 2003; 112: 785–794.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The β-catenin expression vector (β-cat S45A) has been provided by Dr Thilo Hagen (Wolfson Digestive Diseases Centre, University of Nottingham, UK). The plasmids for -65-Luc, pSF-1 and –966Luc (StAR Promoter) were generous gifts from Dr KL Parker (South-western Medical Center, University of Texas, Dallas, USA) and Dr D Stocco (Texas Tech University, Lubbock, USA), respectively. This work was supported by a grant from the Eberhard-Igler-Stiftung and Walter-Clawitter-Stiftung to S Schinner and HS Willenberg and by a grant from the Deutsche Forschungsgemeinschaft (EH 161/4-1) to M Ehrhart-Bornstein and SR Bornstein.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany

    S Schinner, H S Willenberg, D Krause, M Schott & W A Scherbaum

  2. Department of Medicine, Carl Gustav Carus University of Dresden, Dresden, Germany

    V Lamounier-Zepter, A W Krug, M Ehrhart-Bornstein & S R Bornstein

Authors
  1. S Schinner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H S Willenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Schott
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V Lamounier-Zepter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A W Krug
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Ehrhart-Bornstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S R Bornstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. W A Scherbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Schinner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schinner, S., Willenberg, H., Krause, D. et al. Adipocyte-derived products induce the transcription of the StAR promoter and stimulate aldosterone and cortisol secretion from adrenocortical cells through the Wnt-signaling pathway. Int J Obes 31, 864–870 (2007). https://doi.org/10.1038/sj.ijo.0803508

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803508

Keywords

This article is cited by

Search

Advanced search

Quick links