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:

The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss

International Journal of Obesity volume 36, pages 1195–1202 (2012)Cite this article

Subjects

Abstract

Background:

Adipose tissue is critical for systemic metabolic health. Identifying key factors regulating adipose tissue function is a research priority. The NR4A subfamily of nuclear receptors (NRs) (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) has emerged as important proteins in different disease states and in the regulation of metabolic tissues, particularly in liver and muscle. However, the expression of the NR4A members in human adipose tissue has not previously been described, and their target genes are largely unknown.

Objective:

To determine whether the NR4As are differentially expressed in human adipose tissue in obesity, and identify potential NR4A target genes.

Design:

Prospective analysis of s.c. adipose tissue before and 1 year after fat loss, and during in vitro differentiation of primary human preadipocytes. Case-control comparison of omental (OM) adipose tissue.

Subjects:

A total of 13 extremely obese patients undergoing biliopancreatic diversion with duodenal switch for fat loss, 12 extremely obese patients undergoing laparoscopic sleeve gastrectomy and 37 lean individuals undergoing hernia repair or laparotomy were included in the study. Measurements were done by quantitative PCR gene expression analysis of the NR4A members and in silico promoter analysis based on microarray data.

Results:

There was a strong upregulation of the NR4As in extreme obesity and normalization after fat loss. The NR4As were expressed at the highest level in stromal–vascular fraction compared with adipocytes, but were downregulated in both fractions after fat loss. Their expression levels were also significantly higher in OM compared with s.c. adipocytes in obesity. The NR4As were downregulated during differentiation of primary human preadipocytes. Moreover, the NR4As were strongly induced within 30 min of tissue incubation. Finally, promoter analysis revealed potential NR4A target genes involved in stress response, immune response, development and other functions. Our data show altered adipose tissue expression of the NR4As in obesity, suggesting that these stress responsive nuclear receptors may modulate pathogenic potential in humans.

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
Figure 6

Similar content being viewed by others

References

  1. Iozzo P . Viewpoints on the way to the consensus session: where does insulin resistance start? The adipose tissue. Diabetes Care 2009; 32 (Suppl 2): S168–S173.

    Article  CAS  Google Scholar 

  2. Bays HE, Gonzalez-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB et al. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Rev Cardiovasc Ther 2008; 6: 343–368.

    Article  CAS  Google Scholar 

  3. Hotamisligil GS . Inflammation and metabolic disorders. Nature 2006; 444: 860–867.

    Article  CAS  Google Scholar 

  4. Gregor MF, Hotamisligil GS . Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29: 415–445.

    Article  CAS  Google Scholar 

  5. McKenna NJ, O’Malley BW . SnapShot: nuclear receptors I. Cell 2010; 142: 822–822.e1.

    Article  CAS  Google Scholar 

  6. McKenna NJ, O’Malley BW . SnapShot: nuclear receptors II. Cell 2010; 142: 986.e1.

    PubMed  Google Scholar 

  7. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ . Nuclear receptors and lipid physiology: opening the X-files. Science 2001; 294: 1866–1870.

    Article  CAS  Google Scholar 

  8. Sonoda J, Pei L, Evans RM . Nuclear receptors: decoding metabolic disease. FEBS Letters 2008; 582: 2–9.

    Article  CAS  Google Scholar 

  9. Lonard DM, Lanz RB, O’Malley BW . Nuclear receptor coregulators and human disease. Endocr Rev 2007; 28: 575–587.

    Article  CAS  Google Scholar 

  10. O’Malley BW, McKenna NJ . Coactivators and corepressors: what's in a name? Mol Endocrinol 2008; 22: 2213–2214.

    Article  Google Scholar 

  11. Kim MS, Sweeney TR, Shigenaga JK, Chui LG, Moser A, Grunfeld C et al. Tumor necrosis factor and interleukin 1 decrease RXRalpha, PPARalpha, PPARgamma, LXRalpha, and the coactivators SRC-1, PGC-1alpha, and PGC-1beta in liver cells. Metabolism 2007; 56: 267–279.

    Article  CAS  Google Scholar 

  12. Fang C, Yoon S, Tindberg N, Jarvelainen HA, Lindros KO, Ingelman-Sundberg M . Hepatic expression of multiple acute phase proteins and down-regulation of nuclear receptors after acute endotoxin exposure. Biochem Pharmacol 2004; 67: 1389–1397.

    Article  CAS  Google Scholar 

  13. Maruyama K, Tsukada T, Ohkura N, Bandoh S, Hosono T, Yamaguchi K . The NGFI-B subfamily of the nuclear receptor superfamily (review). Int J Oncol 1998; 12: 1237–1243.

    CAS  PubMed  Google Scholar 

  14. Pearen MA, Muscat GEO . Minireview: nuclear hormone receptor 4A signaling: implications for metabolic disease. Mol Endocrinol 2010; 24: 1891–1903.

    Article  CAS  Google Scholar 

  15. Maxwell MA, Muscat GE . The NR4A subgroup: immediate early response genes with pleiotropic physiological roles. Nucl Recept Signal 2006; 4: e002.

    Article  Google Scholar 

  16. van Tiel CM, de Vries CJM . NR4All in the vessel wall. J Steroid Biochem Mol Biol 2011; e-pub ahead of print 26 January 2011.

  17. Zhao Y, Bruemmer D . NR4A orphan nuclear receptors: transcriptional regulators of gene expression in metabolism and vascular biology. Arterioscler Thromb Vasc Biol 2010; 30: 1535–1541.

    Article  CAS  Google Scholar 

  18. Pols TW, Bonta PI, de Vries CJ . NR4A nuclear orphan receptors: protective in vascular disease? Curr Opin Lipidol 2007; 18: 515–520.

    Article  CAS  Google Scholar 

  19. McMorrow JP, Murphy EP . Inflammation: a role for NR4A orphan nuclear receptors? Biochem Soc Trans 2011; 39: 688–693.

    Article  CAS  Google Scholar 

  20. Maira M, Martens C, Batsche E, Gauthier Y, Drouin J . Dimer-specific potentiation of NGFI-B (Nur77) transcriptional activity by the protein kinase A pathway and AF-1-dependent coactivator recruitment. Mol Cell Biol 2003; 23: 763–776.

    Article  CAS  Google Scholar 

  21. Perlmann T, Jansson L . A novel pathway for vitamin A signaling mediated by RXR heterodimerization with NGFI-B and NURR1. Genes Dev 1995; 9: 769–782.

    Article  CAS  Google Scholar 

  22. Dankel SN, Fadnes DJ, Stavrum AK, Stansberg C, Holdhus R, Hoang T et al. Switch from stress response to homeobox transcription factors in adipose tissue after profound fat loss. PLoS One 2010; 5: e11033.

    Article  Google Scholar 

  23. van Harmelen V, Skurk T, Hauner H . Primary culture and differentiation of human adipocyte precursor cells. Methods Mol Med 2005; 107: 125–135.

    CAS  PubMed  Google Scholar 

  24. Fu Y, Luo L, Luo N, Zhu X, Garvey WT . NR4A orphan nuclear receptors modulate insulin action and the glucose transport system: potential role in insulin resistance. J Biol Chem 2007; 282: 31525–31533.

    Article  CAS  Google Scholar 

  25. Au WS, Payne VA, O’Rahilly S, Rochford JJ . The NR4A family of orphan nuclear receptors are not required for adipogenesis. Int J Obes (Lond) 2008; 32: 388–392.

    Article  CAS  Google Scholar 

  26. Chao LC, Bensinger SJ, Villanueva CJ, Wroblewski K, Tontonoz P . Inhibition of adipocyte differentiation by Nur77, Nurr1, and Nor1. Mol Endocrinol 2008; 22: 2596–2608.

    Article  CAS  Google Scholar 

  27. Harman-Boehm I, Bluher M, Redel H, Sion-Vardy N, Ovadia S, Avinoach E et al. Macrophage infiltration into omental versus subcutaneous fat across different populations: effect of regional adiposity and the comorbidities of obesity. J Clin Endocrinol Metab 2007; 92: 2240–2247.

    Article  CAS  Google Scholar 

  28. Kloting N, Fasshauer M, Dietrich A, Kovacs P, Schon MR, Kern M et al. Insulin sensitive obesity. Am J Physiol Endocrinol Metab 2010; 299: E506–E515.

    Article  Google Scholar 

  29. Yamashita S, Tanaka Y, Tsutsumi S, Aburatani H, Minato N, Ihara S . Analysis of mechanism for human gammadelta T cell recognition of nonpeptide antigens. Biochem Biophys Res Commun 2005; 334: 349–360.

    Article  CAS  Google Scholar 

  30. Maxwell MA, Cleasby ME, Harding A, Stark A, Cooney GJ, Muscat GE . Nur77 regulates lipolysis in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear hormone receptor pathway. J Biol Chem 2005; 280: 12573–12584.

    Article  CAS  Google Scholar 

  31. Pei L, Castrillo A, Tontonoz P . Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77. Mol Endocrinol 2006; 20: 786–794.

    Article  CAS  Google Scholar 

  32. Dalmas E, Clement K, Guerre-Millo M . Defining macrophage phenotype and function in adipose tissue. Trends Immunol 2011; 32: 307–314.

    Article  CAS  Google Scholar 

  33. Kim BY, Kim H, Cho EJ, Youn HD . Nur77 upregulates HIF-alpha by inhibiting pVHL-mediated degradation. Exp Mol Med 2008; 40: 71–83.

    Article  CAS  Google Scholar 

  34. Wood IS, de Heredia FP, Wang B, Trayhurn P . Cellular hypoxia and adipose tissue dysfunction in obesity. Proc Nutr Soc 2009; 68: 370–377.

    Article  CAS  Google Scholar 

  35. Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S et al. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 2009; 29: 4467–4483.

    Article  CAS  Google Scholar 

  36. Trayhurn P, Wang B, Wood IS . Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity? Br J Nutr 2008; 100: 227–235.

    Article  CAS  Google Scholar 

  37. Oita RC, Mazzatti DJ, Lim FL, Powell JR, Merry BJ . Whole-genome microarray analysis identifies up-regulation of Nr4a nuclear receptors in muscle and liver from diet-restricted rats. Mech Ageing Dev 2009; 130: 240–247.

    Article  CAS  Google Scholar 

  38. Pols TW, Ottenhoff R, Vos M, Levels JH, Quax PH, Meijers JC et al. Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity. Biochem Biophys Res Commun 2008; 366: 910–916.

    Article  CAS  Google Scholar 

  39. Kolehmainen M, Vidal H, Alhava E, Uusitupa MI . Sterol regulatory element binding protein 1c (SREBP-1c) expression in human obesity. Obes Res 2001; 9: 706–712.

    Article  CAS  Google Scholar 

  40. Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, Tontonoz P . NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism. Nat Med 2006; 12: 1048–1055.

    Article  CAS  Google Scholar 

  41. Kumar N, Liu D, Wang H, Robidoux J, Collins S . Orphan nuclear receptor NOR-1 enhances 3′,5′-cyclic adenosine 5′-monophosphate-dependent uncoupling protein-1 gene transcription. Mol Endocrinol 2008; 22: 1057–1064.

    Article  CAS  Google Scholar 

  42. Fu M, Sun T, Bookout AL, Downes M, Yu RT, Evans RM et al. A nuclear receptor Atlas: 3T3-L1 adipogenesis. Mol Endocrinol 2005; 19: 2437–2450.

    Article  CAS  Google Scholar 

  43. Martinez-Gonzalez J, Badimon L . The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells. Cardiovasc Res 2005; 65: 609–618.

    Article  CAS  Google Scholar 

  44. Tanabe Y, Koga M, Saito M, Matsunaga Y, Nakayama K . Inhibition of adipocyte differentiation by mechanical stretching through ERK-mediated downregulation of PPARgamma2. J Cell Sci 2004; 117 (Part 16): 3605–3614.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the participants who gave blood samples and tissue biopsies. We thank Tone Saeterdal Myhra, Carol Cook and Anita Ivarsflaten for expert technical assistance. We thank the staff at Voss Hospital, Norway for assistance with biopsy collection, in particular Borghild Strønen, Tor Nedrebø, Maria Decap, Beate Tveit, Olav Lødemel, Åse Hommedal and Hege Sunde Jordalen. We thank the staff at Haraldsplass Deaconess Hospital, Bergen, Norway, particularly Drs. Inge Glambek, Barbara Auras Jaatun and Torodd Bruland. This project was funded by Samarbeidsorganet Helse Vest, Meltzerfondet and Programstyret for ernaering at the University of Bergen.

Author information

Author notes

  1. V L Veum and S N Dankel: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Medicine, University of Bergen, Bergen, Norway

    V L Veum, S N Dankel, J Gjerde, M H Solsvik, T Hoang, J V Sagen & G Mellgren

  2. Hormone Laboratory, Haukeland University Hospital, Bergen, Norway

    V L Veum, S N Dankel, J Gjerde, M H Solsvik, C Haugen, T Hoang, J V Sagen & G Mellgren

  3. Department of Surgery, Voss Hospital, Voss, Norway

    H J Nielsen

  4. Department of Surgery, Haukeland University Hospital, Bergen, Norway

    B J Christensen

  5. Department of Surgical Sciences, University of Bergen, Bergen, Norway

    B J Christensen

  6. Department of Medicine, F,

    D J Fadnes

  7. ø,

    D J Fadnes

  8. rde Central Hospital, F, ø, rde, Norway

    D J Fadnes

  9. Teres Medical Group Norge, Klinikk Bergen, Nesttun, Norway

    C Busch

  10. Department of Surgery, F,

    V Våge

  11. ø,

    V Våge

  12. rde Central Hospital, F, ø, rde, Norway

    V Våge

Authors
  1. V L Veum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S N Dankel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Gjerde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H J Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M H Solsvik
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Haugen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. B J Christensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. T Hoang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D J Fadnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Busch
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. V Våge
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J V Sagen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. G Mellgren
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Mellgren.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Veum, V., Dankel, S., Gjerde, J. et al. The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss. Int J Obes 36, 1195–1202 (2012). https://doi.org/10.1038/ijo.2011.240

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2011.240

Keywords

This article is cited by

Search

Advanced search

Quick links