Original Article | Published:

Long-term glucocorticoid concentrations as a risk factor for childhood obesity and adverse body-fat distribution

International Journal of Obesity volume 40, pages 15031509 (2016) | Download Citation

Abstract

Background:

Childhood obesity is an important risk factor for premature development of the metabolic syndrome (MetS) at adulthood. There is need for understanding of the mechanisms underlying the MetS and obesity. Patients with Cushing’s disease suffer from similar metabolic complications, leading to the hypothesis that inter-individual cortisol variation may contribute to the onset of obesity. In addition, glucocorticoid receptor (GR)-gene polymorphisms resulting in differential glucocorticoid (GC) sensitivity, have been associated with an adverse metabolic profile.

Aim:

To study associations of GC levels in scalp hair, as a marker of long-term systemic GC concentrations, and genetically determined GC sensitivity with obesity and body-fat distribution in children.

Methods:

We performed a cross-sectional study of cortisol and cortisone concentrations over a 3-month period, measured by LC-MS/MS (Liquid Chromatography Tandem Mass Spectrometry) in hair of 3019 6-year-old children participating in the Generation R study. Genotyping of GR-gene polymorphisms was performed.

Results:

Of all children, 4.3% was obese and 13.4% overweight. Cortisol was significantly associated with risk of obesity (odd ratio (OR): 9.4 (3.3–26.9)) and overweight (OR: 1.4 (1.0–2.0)). Cortisone was associated with risk of obesity (OR: 1.9 (1.0–3.5)). Cortisol and cortisone were significantly positively associated with body mass index, fat mass (FM) index and android/gynecoid FM ratio. GR polymorphisms were not associated with adiposity parameters.

Conclusion:

Long-term cortisol concentrations are strongly associated with an increased risk of childhood obesity and adverse body-fat distribution. Future research may reveal whether these are causal relations and may be a target for therapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , , , et al. Overweight in children and adolescents: pathophysiology, consequences, prevention, and treatment. Circulation 2005; 111: 1999–2012.

  2. 2.

    , , , . Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA 2012; 307: 483–490.

  3. 3.

    , , , , . Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: a dose-response study. Obes Res 1996; 4: 277–282.

  4. 4.

    , , , , , . Cortisol secretion in relation to body fat distribution in obese premenopausal women. Metabolism 1992; 41: 882–886.

  5. 5.

    , , , , , et al. The hypothalamic–pituitary–adrenal axis in obese women with different patterns of body fat distribution. J Clin Endocrinol Metab 1993; 77: 341–346.

  6. 6.

    , , , , , . Fat distribution in obese women is associated with subtle alterations of the hypothalamic–pituitary–adrenal axis activity and sensitivity to glucocorticoids. Clin Endocrinol (Oxf) 2001; 55: 447–454.

  7. 7.

    , , , , . Increased cortisol bioavailability, abdominal obesity, and the metabolic syndrome in obese women. Obes Res 2005; 13: 1157–1166.

  8. 8.

    , , , . Central adiposity and cortisol responses to waking in middle-aged men and women. Int J Obes Relat Metab Disord 2004; 28: 1168–1173.

  9. 9.

    , , , , . Cortisol metabolism in human obesity: impaired cortisone–cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 1999; 84: 1022–1027.

  10. 10.

    , , , , , et al. Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 1998; 83: 757–760.

  11. 11.

    , , , , , et al. Elevated fasting plasma cortisol is associated with ischemic heart disease and its risk factors in people with type 2 diabetes: the Edinburgh type 2 diabetes study. J Clin Endocrinol Metab 2010; 95: 1602–1608.

  12. 12.

    , , , , . Gender differences in the associations between cortisol and insulin in healthy subjects. J Endocrinol 1996; 149: 313–318.

  13. 13.

    , , , , . Cortisol, obesity, and the metabolic syndrome: a cross-sectional study of obese subjects and review of the literature. Obesity (Silver Spring) 2013; 21: E105–E117.

  14. 14.

    , , . Advances in the assessment of cortisol exposure and sensitivity. Curr Opin Endocrinol Diabetes Obes 2014; 21: 306–311.

  15. 15.

    , , , , . Measurement of cortisol in human hair as a biomarker of systemic exposure. Clin Invest Med 2007; 30: E183–E191.

  16. 16.

    , , , . Evaluation of a method to measure long term cortisol levels. Steroids 2011; 76: 1032–1036.

  17. 17.

    , , , . Salivary cortisone is a potential biomarker for serum free cortisol. J Clin Endocrinol Metab 2010; 95: 4951–4958.

  18. 18.

    , , , , , et al. Cortisol in hair and the metabolic syndrome. J Clin Endocrinol Metab 2013; 98: 2573–2580.

  19. 19.

    , , , , . Shift work at young age is associated with elevated long-term cortisol levels and body mass index. J Clin Endocrinol Metab 2011; 96: E1862–E1865.

  20. 20.

    , , , , . Measurement of cortisol and testosterone in hair of obese and non-obese human subjects. Exp Clin Endocrinol Diabetes. 2014; 122: 356–362.

  21. 21.

    , , , , , et al. Validation and reference ranges of hair cortisol measurement in healthy children. Horm Res Paediat 2014; 82: 97–102.

  22. 22.

    , , , , , et al. Increased scalp hair cortisol concentrations in obese children. J Clin Endocr Metab 2014; 99: 285–290.

  23. 23.

    , , , , , et al. Long-term cortisol levels measured in scalp hair of obese patients. Obesity (Silver Spring) 2014; 22: 1956–1958.

  24. 24.

    , , , , , et al. High long-term cortisol levels, measured in scalp hair, are associated with a history of cardiovascular disease. J Clin Endocrinol Metab 2013; 98: 2078–2083.

  25. 25.

    , , , , , et al. A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes 2002; 51: 3128–3134.

  26. 26.

    , , , , , et al. The ER22/23EK polymorphism in the glucocorticoid receptor gene is associated with a beneficial body composition and muscle strength in young adults. J Clin Endocrinol Metab. 2004; 89: 4004–4009.

  27. 27.

    , , , , , et al. A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 1998; 83: 144–151.

  28. 28.

    , , , . The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. J Clin Endocrinol Metab 2001; 86: 2270–2274.

  29. 29.

    , , , , , . The N363S polymorphism in the glucocorticoid receptor gene is associated with overweight in subjects with type 2 diabetes mellitus. Clin Endocrinol (Oxf) 2003; 59: 237–241.

  30. 30.

    , , , , , et al. The Generation R Study: Biobank update 2015. Eur J Epidemiol 2014; 29: 911–927.

  31. 31.

    , , , . Establishing a standard definition for child overweight and obesity worldwide: international survey. Brit Med J 2000; 320: 1240–1243.

  32. 32.

    , , , , . LC-MS/MS-based method for long-term steroid profiling in human scalp hair. Clin Endocrinol (Oxf) 2015; 83: 162–166.

  33. 33.

    , , , , , et al. Glucocorticoid receptor gene polymorphisms do not affect growth in fetal and early postnatal life. The Generation R Study. BMC Med Genet 2010; 11: 39.

  34. 34.

    R Core Team, R Foundation for Statistical Computing. R: a language and environment for statistical computing. Available at: . 2013.

  35. 35.

    , . Mice: multivariate Imputation by chained equations in R. J Stat Softw 2011; 45: 1–67.

  36. 36.

    , , , , , et al. Challenges in conducting genome-wide association studies in highly admixed multi-ethnic populations: the generation R Study. Eur J Epidemiol 2015; 30: 317–330.

  37. 37.

    , , , , , et al. Long-term cortisol levels measured in scalp hair of obese patients. Obesity 2014; 22: 1956–1958.

  38. 38.

    , , , , , et al. BclI glucocorticoid receptor polymorphism is associated with greater body fatness: the Hoorn and CODAM studies. J Clin Endocrinol Metab 2013; 98: E595–E599.

  39. 39.

    , , , . Associations of glucocorticoid receptor and corticosteroid-binding globulin gene polymorphisms on fat mass and fat mass distribution in prepubertal obese children. J Physiol Biochem 2012; 68: 645–650.

  40. 40.

    , , , , , et al. Glucocorticoid receptor gene variant is associated with increased body fatness in youngsters. Clin Endocrinol (Oxf) 2009; 71: 518–523.

  41. 41.

    , , , , , et al. Glucocorticoid receptor gene haplotypes are not associated with birth anthropometry, blood pressure, glucose and insulin concentrations, and body composition in subjects born small for gestational age. Eur J Endocrinol 2010; 163: 911–918.

  42. 42.

    , , , , , et al. Role of mineralocorticoid receptors on the hypothalamus–pituitary–adrenal axis in humans. Endocrine 2013; 43: 51–58.

  43. 43.

    , , , , . Mineralocorticoid and glucocorticoid receptor balance in control of HPA axis and behaviour. Psychoneuroendocrinology 2013; 38: 648–658.

  44. 44.

    , , , , , et al. Body mass index, total and abdominal fat distribution and cardiovascular risk factors in school-age children. Pediatr Res 2015; 77: 710–718.

  45. 45.

    , . Requirement for mass spectrometry sex steroid assays in the Journal of Clinical Endocrinology and Metabolism. J Clin Endocrinol Metab 2013; 98: 3971–3973.

  46. 46.

    , . Systemic glucocorticoid therapy: a review of its metabolic and cardiovascular adverse events. Drugs 2014; 74: 1731–1745.

Download references

Acknowledgements

We are grateful for the financial support by the Thrasher Research Fund (Grant TRF-11643), which enabled this research project. The general design of Generation R Study is made possible by financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Health Research and Development (ZonMw), the Netherlands Organisation for Scientific Research (NWO), the Ministry of Health, Welfare and Sport and the Ministry of Youth and Families. Vincent Jaddoe received an additional grant from the Netherlands Organisation for Scientific Research (NWO, ZonMW-VIDI). Elisabeth van Rossum is additionally supported by a grant of the Netherlands Brain Foundation (F2011(1)-12) and an Erasmus MC Fellowship. The analytical support of Mrs. Kristien Dorst has been greatly appreciated.

Author information

Affiliations

  1. Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    • G Noppe
    • , Y B de Rijke
    • , J W Koper
    •  & E F C van Rossum
  2. Obesity Center CGG, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    • G Noppe
    • , E L T van den Akker
    • , Y B de Rijke
    • , J W Koper
    •  & E F C van Rossum
  3. The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    • G Noppe
    •  & V W Jaddoe
  4. Department of Pediatrics, Sophia Children's Hospital, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    • E L T van den Akker
    •  & V W Jaddoe
  5. Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    • Y B de Rijke
  6. Department of Epidemiology and Biostatistics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

    • V W Jaddoe

Authors

  1. Search for G Noppe in:

  2. Search for E L T van den Akker in:

  3. Search for Y B de Rijke in:

  4. Search for J W Koper in:

  5. Search for V W Jaddoe in:

  6. Search for E F C van Rossum in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to E F C van Rossum.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/ijo.2016.113

Supplementary Information accompanies this paper on International Journal of Obesity website (http://www.nature.com/ijo)

Further reading