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Allelic variants in the GABAAα6 receptor subunit gene (GABRA6) is associated with abdominal obesity and cortisol secretion

International Journal of Obesity volume 26, pages 938–941 (2002)Cite this article

Abstract

Introduction: Cortisol is involved in the regulation of adipose-tissue differentiation, function and distribution, and in excess causes abdominal obesity. At the level of the brain, cortisol secretion is partly controlled by γ-aminobutyric acid (GABA), which is the major inhibitory neurotransmitter in the vertebrate brain, and acts by binding to GABAA receptors.

Method: We examined the potential impact of a 1519T>C polymorphism in the GABAAα6 receptor subunit (GABRA6) gene on obesity and obesity-related phenotypes as well as circulating hormones, including salivary cortisol in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of the 3′ non-coding region of the GABRA6 gene followed by digestion with the restriction enzyme AlwNI.

Results: The frequency of allele T was 0.54 and 0.46 for allele C. Carriers for the T allele (n=211) had borderline significantly higher waist-to-hip ratio (P=0.094) and abdominal sagittal diameter (P=0.084) compared to homozygotes for the C allele (n=56). The homozygotes for the T allele had, in comparison to heterozygotes, significantly (P=0.004–0.024) higher mean cortisol levels at 11:45 am, and 30, 45 and 60 min after a standardized lunch and, finally, at 5:00 pm. In addition, T/T subjects had significantly (P=0.031) higher diurnal cortisol secretion compared to T/C subjects. Other hormones, glucose and serum lipids were not different across the genotype groups.

Conclusion: These findings suggest a role of the 1519T>C polymorphism in GABRA6 in the predisposition to hypercortisolism and perhaps abdominal obesity. The pathophysiology may involve various environmental factors, particularly stress, that destabilize the GABA–hypothalamic–pituitary–adrenal systems in those with genetic vulnerability.

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References

  1. Chrousos GP . Stressors, stress, and neuroendocrine integration of the adaptive response. The 1997 Hans Selye Memorial Lecture Ann NY Acad Sci 1998 851: 311–335.

    Article  CAS  Google Scholar 

  2. Björntorp P, Rosmond R . Hypothalamic origin of the metabolic syndrome X Ann NY Acad Sci 1999 892: 297–307.

    Article  Google Scholar 

  3. Björntorp P, Rosmond R . Obesity and cortisol Nutrition 2000 16: 924–936.

    Article  Google Scholar 

  4. Dornhorst A, Carlson DE, Seif SM, Robinson AG, Zimmerman EA, Gann DS . Control of release of adrenocorticotropin and vasopressin by the supraoptic and paraventricular nuclei Endocrinology 1981 108: 1420–1424.

    Article  CAS  Google Scholar 

  5. Grossman A, Costa A . The regulation of hypothalamic CRH: impact of in vitro studies on the central control of the stress response Funct Neurol 1993 8: 325–334.

    CAS  PubMed  Google Scholar 

  6. Ward DG, Bolton MG, Gann DS . Inhibitory and facilitatory areas of the ventral midbrain mediating release of corticotropin in the cat Endocrinology 1978 102: 1147–1154.

    Article  CAS  Google Scholar 

  7. Carlson DE, Dornhorst A, Gann DS . Organization of the lateral hypothalamus for control of adrenocorticotropin release in the cat Endocrinology 1980 107: 961–969.

    Article  CAS  Google Scholar 

  8. Calogero AE, Gallucci WT, Chrousos GP, Gold PW . Interaction between GABAergic neurotransmission and rat hypothalamic corticotropin-releasing hormone secretion in vitro Brain Res 1988 463: 28–36.

    Article  CAS  Google Scholar 

  9. Chebib M, Johnston GA . The ‘ABC’ of GABA receptors: a brief review Clin Exp Pharmac Physiol 1999 26: 937–940.

    Article  CAS  Google Scholar 

  10. Curtis GC, Abelson JL, Gold PW . Adrenocorticotropic hormone and cortisol responses to corticotropin-releasing hormone: changes in panic disorder and effects of alprazolam treatment Biol Psychiat 1997 41: 76–85.

    Article  CAS  Google Scholar 

  11. Arvat E, Maccagno B, Ramunni J, Di Vito L, Giordano R, Gianotti L et al. The inhibitory effect of alprazolam, a benzodiazepine, overrides the stimulatory effect of metyrapone-induced lack of negative cortisol feedback on corticotroph secretion in humans J Clin Endocrinol Metab 1999 84: 2611–2615.

    CAS  PubMed  Google Scholar 

  12. Grottoli S, Arvat E, Gauna C, Maccagno B, Ramunni J, Giordano R et al. Alprazolam, a benzodiazepine, blunts but does not abolish the ACTH and cortisol response to hexarelin, a GHRP, in obese patients Int J Obes Relat Metab Disord 2000 24: S136–S137.

    Article  CAS  Google Scholar 

  13. Loh EW, Smith I, Murray R, McLaughlin M, McNulty S, Ball D . Association between variants at the GABAAβ2, GABAAα6 and GABAAγ2 gene cluster and alcohol dependence in a Scottish population Mol Psychiat 1999 4: 539–544.

    Article  CAS  Google Scholar 

  14. Hicks AA, Bailey ME, Riley BP, Kamphuis W, Siciliano MJ, Johnson KJ et al. Further evidence for clustering of human GABAA receptor subunit genes: localization of the alpha 6-subunit gene (GABRA6) to distal chromosome 5q by linkage analysis Genomics 1994 20: 285–288.

    Article  CAS  Google Scholar 

  15. Brailowsky S, Garcia O . Ethanol, GABA and epilepsy Arch Med Res 1999 30: 3–9.

    Article  CAS  Google Scholar 

  16. Rosmond R, Lapidus L, Mårin P, Björntorp P . Mental distress, obesity and body fat distribution in middle-aged men Obes Res 1996 4: 245–252.

    Article  CAS  Google Scholar 

  17. Rosmond R, Lapidus L, Björntorp P . The influence of occupational and social factors on obesity and body fat distribution in middle-aged men Int J Obes Relat Metab Disord 1996 20: 599–607.

    CAS  PubMed  Google Scholar 

  18. Rosmond R, Dallman MF, Björntorp P . Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities J Clin Endocrinol Metab 1998 83: 1853–1859.

    CAS  PubMed  Google Scholar 

  19. Rosmond R, Chagnon YC, Holm G, Chagnon M, Perusse L, Lindell K et al. Hypertension in obesity and the leptin receptor gene locus J Clin Endocrinol Metab 2000 85: 3126–3131.

    CAS  PubMed  Google Scholar 

  20. Spjotvoll E, Stoline M . An extension of the T-method of multiple comparison to include the cases with unequal sample sizes J Am Stat Assoc 1973 68: 976–978.

    Google Scholar 

  21. Björntorp P . The associations between obesity, adipose tissue distribution and disease Acta Med Scand 1988 723 (Suppl): 121–134.

    Google Scholar 

  22. Reaven GM . Banting lecture 1988. Role of insulin resistance in human disease Diabetes 1988 37: 1595–1607.

    Article  CAS  Google Scholar 

  23. Bouchard C . Genetics of obesity: an update on molecular markers Int J Obes Relat Metab Disord 1995 19: S10–S13.

    PubMed  Google Scholar 

  24. Perusse L, Chagnon YC, Weisnagel SJ, Rankinen T, Synder E, Sands J et al. The human obesity gene map: the 2000 update Obes Res 2001 9: 135–169.

    Article  CAS  Google Scholar 

  25. Coscina DV, Castonguay TW, Stern JS . Effects of increasing brain GABA on the meal patterns of genetically obese vs. lean Zucker rats Int J Obes Relat Metab Disord 1992 16: 425–433.

    CAS  PubMed  Google Scholar 

  26. Orosco M, Jacquot C, Wepierre J, Cohen Y . GABA levels and synthesis index in different brain areas of two obese rat models Gen Pharmac 1981 12: 369–371.

    Article  CAS  Google Scholar 

  27. Ebert MH, Schmidt DE, Thompson T, Butler MG . Elevated plasma gamma-aminobutyric acid (GABA) levels in individuals with either Prader–Willi syndrome or Angelman syndrome J Neuropsychiat Clin Neurosci 1997 9: 75–80.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by grants from the Swedish Medical Research Council (K97-19X-00251-35A) and the Pennington Biomedical Research Center. R Rosmond would also like to acknowledge the Henning and Johan Throne-Holst Foundation for the support of a postdoctoral fellowship at the Pennington Biomedical Research Center. C Bouchard is partially supported by the George A Bray Chair in Nutrition.

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Authors and Affiliations

  1. Department of Clinical Chemistry, Sahlgrenska University Hospital, Göteborg, Sweden

    R Rosmond

  2. Pennington Biomedical Research Center, Baton Rouge, Lousiana, USA

    R Rosmond & C Bouchard

  3. Department of Heart and Lung Diseases, Sahlgrenska University Hospital, Göteborg, Sweden

    P Björntorp

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  1. R Rosmond
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  2. C Bouchard
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  3. P Björntorp
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Rosmond, R., Bouchard, C. & Björntorp, P. Allelic variants in the GABAAα6 receptor subunit gene (GABRA6) is associated with abdominal obesity and cortisol secretion. Int J Obes 26, 938–941 (2002). https://doi.org/10.1038/sj.ijo.0802022

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