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  • Original Article
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Pediatrics

Impairment of adipose tissue in Prader–Willi syndrome rescued by growth hormone treatment

Abstract

Background:

Prader–Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment.

Objectives:

Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment.

Subjects and methods:

Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children.

Results:

Children with PWS displayed higher insulin sensitivity as shown by reduced glycemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared with control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to β-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment.

Conclusion:

Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.

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References

  1. Whittington JE, Holland AJ, Webb T, Butler J, Clarke D, Boer H . Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region. J Med Genet 2001; 38: 792–798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Smith A, Egan J, Ridley G, Haan E, Montgomery P, Williams K et al Birth prevalence of Prader-Willi syndrome in Australia. Arch Dis Child 2003; 88: 263–264.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Vogels A, Van Den Ende J, Keymolen K, Mortier G, Devriendt K, Legius E et al Minimum prevalence, birth incidence and cause of death for Prader-Willi syndrome in Flanders. Eur J Hum Genet 2004; 12: 238–240.

    CAS  PubMed  Google Scholar 

  4. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ . Prader-Willi syndrome. Genet Med 2012; 14: 10–26.

    Article  CAS  PubMed  Google Scholar 

  5. Horsthemke B, Wagstaff J . Mechanisms of imprinting of the Prader-Willi/Angelman region. Am J Med Genet A 2008; 146A: 2041–2052.

    CAS  PubMed  Google Scholar 

  6. Nicholls RD, Knepper JL . Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet 2001; 2: 153–175.

    Article  CAS  PubMed  Google Scholar 

  7. Goldstone AP . Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab 2004; 15: 12–20.

    Article  CAS  PubMed  Google Scholar 

  8. Butler JV, Whittington JE, Holland AJ, McAllister CJ, Goldstone AP . The transition between the phenotypes of Prader-Willi syndrome during infancy and early childhood. Dev Med Child Neurol 2010; 52: e88–e93.

    Article  PubMed  Google Scholar 

  9. Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V et al Nutritional phases in Prader-Willi syndrome. Am J Med Genet A 2011; 155A: 1040–1049.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mc Cune H, Driscoll D . Prader-Willi syndrome. In: Ekvall S, Ekvall VK (eds). Pediatric Nutrition in Chronic Disease and Developmental Disorders. Oxford University Press: New York, NY, USA, 2005. pp128–132.

    Google Scholar 

  11. Swaab DF . Prader-Willi syndrome and the hypothalamus. Acta Paediatr Suppl 1997; 423: 50–54.

    Article  CAS  PubMed  Google Scholar 

  12. Costeff H, Holm VA, Ruvalcaba R, Shaver J . Growth hormone secretion in Prader-Willi syndrome. Acta Paediatr Scand 1990; 79: 1059–1062.

    Article  CAS  PubMed  Google Scholar 

  13. Burman P, Ritzen EM, Lindgren AC . Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Endocr Rev 2001; 22: 787–799.

    Article  CAS  PubMed  Google Scholar 

  14. Diene G, Mimoun E, Feigerlova E, Caula S, Molinas C, Grandjean H et al Endocrine disorders in children with Prader-Willi syndrome—data from 142 children of the French database. Horm Res Paediatr 2010; 74: 121–128.

    Article  CAS  PubMed  Google Scholar 

  15. Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M . Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab 2008; 93: 4183–4197.

    Article  CAS  PubMed  Google Scholar 

  16. Brambilla P, Bosio L, Manzoni P, Pietrobelli A, Beccaria L, Chiumello G . Peculiar body composition in patients with Prader-Labhart-Willi syndrome. Am J Clin Nutr 1997; 65: 1369–1374.

    Article  CAS  PubMed  Google Scholar 

  17. Theodoro MF, Talebizadeh Z, Butler MG . Body composition and fatness patterns in Prader-Willi syndrome: comparison with simple obesity. Obesity (Silver Spring) 2006; 14: 1685–1690.

    Article  Google Scholar 

  18. Eiholzer U, Blum WF, Molinari L . Body fat determined by skinfold measurements is elevated despite underweight in infants with Prader-Labhart-Willi syndrome. J Pediatr 1999; 134: 222–225.

    Article  CAS  PubMed  Google Scholar 

  19. Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, Cassidy SB, Schrander JJ, Fryns JP . Prader-Willi syndrome: causes of death in an international series of 27 cases. Am J Med Genet A 2004; 124A: 333–338.

    Article  PubMed  Google Scholar 

  20. Arner P . Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 2005; 19: 471–482.

    Article  CAS  PubMed  Google Scholar 

  21. Olefsky JM, Glass CK . Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010; 72: 219–246.

    Article  CAS  PubMed  Google Scholar 

  22. Harant I, Beauville M, Crampes F, Riviere D, Tauber MT, Tauber JP et al Response of fat cells to growth hormone (GH): effect of long term treatment with recombinant human GH in GH-deficient adults. J Clin Endocrinol Metab 1994; 78: 1392–1395.

    CAS  PubMed  Google Scholar 

  23. Le Cao KA, Boitard S, Besse P . Sparse PLS discriminant analysis: biologically relevant feature selection and graphical displays for multiclass problems. BMC Bioinformatics 2011; 12: 253.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Carrel AL, Myers SE, Whitman BY, Allen DB . Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study. J Pediatr 1999; 134: 215–221.

    Article  CAS  PubMed  Google Scholar 

  25. Carrel AL, Myers SE, Whitman BY, Allen DB . Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study. J Clin Endocrinol Metab 2002; 87: 1581–1585.

    Article  CAS  PubMed  Google Scholar 

  26. Hoybye C, Hilding A, Jacobsson H, Thoren M . Growth hormone treatment improves body composition in adults with Prader-Willi syndrome. Clin Endocrinol (Oxf) 2003; 58: 653–661.

    Article  CAS  Google Scholar 

  27. Marzullo P, Marcassa C, Campini R, Eleuteri E, Minocci A, Priano L et al The impact of growth hormone/insulin-like growth factor-I axis and nocturnal breathing disorders on cardiovascular features of adult patients with Prader-Willi syndrome. J Clin Endocrinol Metab 2005; 90: 5639–5646.

    Article  CAS  PubMed  Google Scholar 

  28. Haqq AM, Muehlbauer MJ, Newgard CB, Grambow S, Freemark M . The metabolic phenotype of Prader-Willi syndrome (PWS) in childhood: heightened insulin sensitivity relative to body mass index. J Clin Endocrinol Metab 2011; 96: E225–E232.

    Article  CAS  PubMed  Google Scholar 

  29. Schuster DP, Osei K, Zipf WB . Characterization of alterations in glucose and insulin metabolism in Prader-Willi subjects. Metabolism 1996; 45: 1514–1520.

    Article  CAS  PubMed  Google Scholar 

  30. Hauffa BP, Haase K, Range IM, Unger N, Mann K, Petersenn S . The effect of growth hormone on the response of total and acylated ghrelin to a standardized oral glucose load and insulin resistance in children with Prader-Willi syndrome. J Clin Endocrinol Metab 2007; 92: 834–840.

    Article  CAS  PubMed  Google Scholar 

  31. Goldstone AP, Thomas EL, Brynes AE, Bell JD, Frost G, Saeed N et al Visceral adipose tissue and metabolic complications of obesity are reduced in Prader-Willi syndrome female adults: evidence for novel influences on body fat distribution. J Clin Endocrinol Metab 2001; 86: 4330–4338.

    Article  CAS  PubMed  Google Scholar 

  32. Kennedy L, Bittel DC, Kibiryeva N, Kalra SP, Torto R, Butler MG . Circulating adiponectin levels, body composition and obesity-related variables in Prader-Willi syndrome: comparison with obese subjects. Int J Obes (Lond) 2006; 30: 382–387.

    Article  CAS  Google Scholar 

  33. Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ . Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 1996; 45: 633–638.

    Article  CAS  PubMed  Google Scholar 

  34. Frayn KN . Adipose tissue as a buffer for daily lipid flux. Diabetologia 2002; 45: 1201–1210.

    Article  CAS  PubMed  Google Scholar 

  35. Hoybye C . Inflammatory markers in adults with Prader-Willi syndrome before and during 12 months growth hormone treatment. Horm Res 2006; 66: 27–32.

    PubMed  Google Scholar 

  36. Viardot A, Sze L, Purtell L, Sainsbury A, Loughnan G, Smith E et al Prader-Willi syndrome is associated with activation of the innate immune system independently of central adiposity and insulin resistance. J Clin Endocrinol Metab 2010; 95: 3392–3399.

    Article  CAS  PubMed  Google Scholar 

  37. Hoybye C, Hilding A, Marcus C, Thoren M . Growth hormone induced lipolysis during short- and long-term administration in adult Prader-Willi patients. Growth Horm IGF Res 2005; 15: 411–415.

    Article  PubMed  Google Scholar 

  38. Marcus C, Bolme P, Karpe B, Bronnegard M, Sellden H, Arner P . Expression of beta 1- and beta 2-receptor genes and correlation to lipolysis in human adipose tissue during childhood. J Clin Endocrinol Metab 1993; 76: 879–884.

    CAS  PubMed  Google Scholar 

  39. Bush JR, Wevrick R . Loss of the Prader-Willi obesity syndrome protein necdin promotes adipogenesis. Gene 2012; 497: 45–51.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by grants from the French ministry of health (Programme Hospitalier de Recherche Clinique) and from the Région Midi-Pyrénées. We thank the Anexplo platform for Luminex analyses and are deeply grateful to the children participating in this study, their families and medical staff who performed children recruitment, clinical data collection and tissue sampling. National Program for Clinical Research from the French government (grant 0811601) and Clinical Research Program of Midi-Pyrénées (grant 09004797).

AUTHOR CONTRIBUTIONS

GD, JPS, MT and PV designed the study and conceived experiments. FD, CM, SE and FCA performed data collection. TC, MB, CS and DD carried out experiments. TC, MB, CS, AB, PM analyzed and interpreted data. All authors were involved in writing the paper and had final approval of the submitted and published versions.

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Correspondence to P Valet.

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Cadoudal, T., Buléon, M., Sengenès, C. et al. Impairment of adipose tissue in Prader–Willi syndrome rescued by growth hormone treatment. Int J Obes 38, 1234–1240 (2014). https://doi.org/10.1038/ijo.2014.3

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