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:

Genetics and Epigenetics

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene–diet interactions

International Journal of Obesity volume 37, pages 1499–1505 (2013)Cite this article

Subjects

Abstract

Objective:

Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing.

Design and subjects:

THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial).

Results:

The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10−5). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05–6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d−1), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity.

Conclusions:

THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

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

Similar content being viewed by others

References

  1. Hu FB . Obesity epidemiology. Oxford Univ Press: New York, 2008.

    Book  Google Scholar 

  2. Berrington de Gonzalez A, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ et al. Body-mass index and mortality among 1.46 million white adults. N Engl J Med 2010; 363: 2211–2219.

    Article  CAS  Google Scholar 

  3. McCarthy M . Genomics, type 2 diabetes, and obesity. N Engl J Med 2010; 363: 2339–2350.

    Article  CAS  Google Scholar 

  4. O'Rahilly S . Human genetics illuminates the paths to metabolic disease. Nature 2009; 462: 307–314.

    Article  CAS  Google Scholar 

  5. Maes HH, Neale MC, Eaves LJ . Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997; 27: 325–351.

    Article  CAS  Google Scholar 

  6. Speliotes EK, Willer CJ, Berndt SI, Speliotes EK, Willer CJ, Berndt SI et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–948.

    Article  CAS  Google Scholar 

  7. Kokkoris P, Pi-Sunyer FX . Obesity and endocrine disease. Endocrinol Metab Clin North Am 2003; 32: 895–914.

    Article  CAS  Google Scholar 

  8. Reinehr T . Obesity and thyroid function. Mol Cell Endocrinol 2010; 316: 165–171.

    Article  CAS  Google Scholar 

  9. Biondi B . Thyroid and obesity: an intriguing relationship. J Clin Endocrinol Metab 2010; 95: 3614–3617.

    Article  CAS  Google Scholar 

  10. Knudsen N, Laurberg P, Rasmussen LB, Bülow I, Perrild H, Ovesen L et al. Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab 2005; 90: 4019–4024.

    Article  CAS  Google Scholar 

  11. Fox CS, Pencina MJ, D’Agostino RB, Murabito JM, Seely EW, Pearce EN et al. Relations of thyroid function to body weight: cross-sectional and longitudinal observations in a community- based sample. Arch Intern Med 2008; 168: 587–592.

    Article  Google Scholar 

  12. Manji N, Boelaert K, Sheppard MC, Holder RL, Gough SC, Franklyn JA . Lack of association between serum TSH or free T4 and body mass index in euthyroid subjects. Clin Endocrinol 2006; 64: 125–128.

    Article  CAS  Google Scholar 

  13. Jiang W, Miyamoto T, Kakizawa T, Sakuma T, Nishio S, Takeda T et al. Expression of thyroid hormone receptor alpha in 3T3-L1 adipocytes; triiodothyronine increases the expression of lipogenic enzyme and triglyceride accumulation. J Endocrinol 2004; 182: 295–302.

    Article  CAS  Google Scholar 

  14. Ying H, Araki O, Furuya F, Kato Y, Cheng SY . Impaired adipogenesis caused by a mutated thyroid hormone alpha1 receptor. Mol Cell Biol 2007; 27: 2359–2371.

    Article  CAS  Google Scholar 

  15. Alevizaki M, Saltiki K, Voidonikola P, Mantzou E, Papamichael C, Stamatelopoulos K . Free thyroxine is an independent predictor of subcutaneous fat in euthyroid individuals. Eur J Endocrinol 2009; 161: 459–465.

    Article  CAS  Google Scholar 

  16. Forrest D, Sjoberg M, Vennstrom B . Contrasting developmental and tissue-specific expression of alpha and beta thyroid hormone receptor genes. EMBO J 1990; 9: 1519–1528.

    Article  CAS  Google Scholar 

  17. Kahaly GJ, Dillmann WH . Thyroid hormone action in the heart. Endocr Rev 2005; 26: 704–728.

    Article  CAS  Google Scholar 

  18. Wikström L, Johansson C, Saltó C, Barlow C, Campos Barros A, Baas F et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 1998; 17: 455–461.

    Article  Google Scholar 

  19. Cheng SY, Leonard JL, Davis PJ . Molecular aspects of thyroid hormone actions. Endocr Rev 2010; 31: 139–170.

    Article  CAS  Google Scholar 

  20. Reyne Y, Nougues J, Cambon B, Viguerie-Bascands N, Casteilla L . Expression of c-erbA alpha, c-erbA beta and Rev-erbA alpha mRNA during the conversion of brown adipose tissue into white adipose tissue. Mol Cell Endocrinol 1996; 116: 59–65.

    Article  CAS  Google Scholar 

  21. Weiss RE, Murata Y, Cua K, Hayashi Y, Seo H, Refetoff S . Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice. Endocrinology 1998; 139: 4945–4952.

    Article  CAS  Google Scholar 

  22. Lazar MA . Thyroid hormone receptors: multiple forms, multiple possibilities. Endocr Rev 1993; 14: 184–193.

    CAS  PubMed  Google Scholar 

  23. Lazar MA, Chin WW . Nuclear thyroid hormone receptors. J Clin Invest 1990; 86: 1777–1782.

    Article  CAS  Google Scholar 

  24. Burman KD, Latham KR, Djuh YY, Smallridge RC, Tseng YC, Lukes YG et al. Solubilized nuclear thyroid hormone receptors in circulating human mononuclear cells. J Clin Endocrinol Metab 1980; 51: 106–116.

    Article  CAS  Google Scholar 

  25. Reinehr T, Andler W . Thyroid hormones before and after weight loss in obesity. Arch Dis Child 2002; 87: 320–323.

    Article  CAS  Google Scholar 

  26. Reinehr T, de Sousa G, Andler W . Hyperthyrotropinemia in obese children is reversible afterweight loss and is not related to lipids. J Clin Endocrinol Metab 2006; 91: 3088–3091.

    Article  CAS  Google Scholar 

  27. Valdés S, Botas P, Delgado E, Alvarez F, Cadórniga FD . Population-based incidence of type 2 diabetes in northern Spain: the Asturias Study. Diabetes Care 2007; 30: 2258–2263.

    Article  Google Scholar 

  28. Moreno-Navarrete JM, Ortega FJ, Bassols J, Castro A, Ricart W, Fernández-Real JM . Association of circulating lactoferrin concentration and 2 nonsynonymous LTF gene polymorphisms with dyslipidemia in men depends on glucose-tolerance status. Clin Chem 2008; 54: 301–309.

    Article  CAS  Google Scholar 

  29. Martinez-Larrad MT, Fernandez-Perez C, Gonzalez-Sanchez JL, Gonzalez-Sanchez JL, López A, Fernández-Alvarez J et al. Prevalence of the metabolic syndrome (ATP-III criteria). Population-based study of rural and urban areas in the Spanish province of Segovia. Med Clin (Barc) 2005; 125: 481–486.

    Article  Google Scholar 

  30. Soriguer F, Rojo-Martinez G, Almaraz MC, Esteva I, Ruiz de Adana MS, Morcillo S et al. Incidence of type 2 diabetes in southern Spain (Pizarra study). Eur J Clin Invest 2008; 38: 126–133.

    Article  CAS  Google Scholar 

  31. The World Health Organization Monica Project. Ecological analysis of the association between mortality and major risk factors of cardiovascular disease. Int J Epidemiol 1994; 23: 505–516.

  32. Estruch R, Martínez-González MA, Corella D, Salas-Salvadó J, Ruiz-Gutiérrez V, Covas MI et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006; 145: 1–11.

    Article  Google Scholar 

  33. Gonzalez JR, Armengol L, Sole X, Guinó E, Mercader JM, Estivill X et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics 2007; 23: 644–645.

    PubMed  Google Scholar 

  34. Balding DJ . A tutorial on statistical methods for population association studies. Nat Rev Genet 2006; 7: 781–791.

    Article  CAS  Google Scholar 

  35. Hastings ML, Wilson CM, Munroe SH . A purine-rich intronic element enhances alternative splicing of thyroid hormone receptor mRNA. RNA 2001; 7: 859–874.

    Article  CAS  Google Scholar 

  36. Liu YY, Schultz JJ, Brent GA . A thyroid hormone receptor gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. J Biol Chem 2003; 278: 38913–38920.

    Article  CAS  Google Scholar 

  37. Sjogren M, Alkemade A, Mittag J, Nordström K, Katz A, Rozell B et al. Hypermetabolism in mice caused by the central action of an unliganded thyroid hormone receptor α1. EMBO J 2007; 26: 4535–4545.

    Article  Google Scholar 

  38. Pelletier P, Gauthier K, Sideleva O, Samarut J, Silva JE . Mice lacking the thyroid hormone receptor-alpha gene spend more energy in thermogenesis, burn more fat, and are less sensitive to high-fat diet-induced obesity. Endocrinology 2008; 149: 6471–6486.

    Article  CAS  Google Scholar 

  39. Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA, Tang V et al. Leptin directly activatesSF-1 neurons in the VMH and this action by leptin is required for normal body weight homeostasis. Neuron 2006; 49: 191–203.

    Article  CAS  Google Scholar 

  40. Decherf S, Seugnet I, Kouidhi S, Lopez-Juarez A, Clerget-Froidevaux MS, Demeneix BA . Thyroid hormone exerts negative feedback on hypothalamic type 4 melanocortin receptor expression. Proc Natl Acad Sci USA 2010; 107: 4471–4476.

    Article  CAS  Google Scholar 

  41. Coppola A, Liu ZW, Andrews ZB, Paradis E, Roy MC, Friedman JM et al. A central thermogenic-like mechanism in feeding regulation: an interplay between arcuate nucleus T3 and UCP2. Cell Metab 2007; 5: 21–33.

    Article  CAS  Google Scholar 

  42. Villicev CM, Freitas FR, Aoki MS, Taffarel C, Scanlan TS, Moriscot AS et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat mass accumulation in rats. J Endocrinol 2007; 193: 21–29.

    Article  CAS  Google Scholar 

  43. Mitchell CS, Savage DB, Dufour S, Schoenmakers N, Murgatroyd P, Befroy D et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest 2010; 120: 1345–1354.

    Article  CAS  Google Scholar 

  44. Suzuki T, Mochizuki K, Goda T . Localized expression of genes related to carbohydrate and lipid absorption along the crypt-villus axis of rat jejunum. Biochim Biophys Acta 2009; 1790: 1624–1635.

    Article  CAS  Google Scholar 

  45. Mochizuki K, Yagi E, Sakaguchi N, Mochizuki H, Takabe S, Kuranuki S et al. The critical period for thyroid hormone responsiveness through thyroid hormone receptor isoform alpha in the postnatal small intestine. Biochim Biophys Acta 2007; 1770: 609–616.

    Article  CAS  Google Scholar 

  46. Ladenson PW, Kristensen JD, Ridgway EC, Olsson AG, Carlsson B, Klein I et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 2010; 362: 906–916.

    Article  CAS  Google Scholar 

  47. Pearce EN . Hypothyroidism and dyslipidemia: modern concepts and approaches. Curr Cardiol Rep 2004; 6: 451–456.

    Article  Google Scholar 

  48. Ortega FJ, Moreno-Navarrete JM, Ribas V, Esteve E, Rodriguez-Hermosa JI, Ruiz B et al. Subcutaneous fat shows higher thyroid hormone receptor-alpha1 gene expression than omental fat. Obesity (Silver Spring) 2009; 17: 2134–2141.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We greatly appreciate the technical assistance of Gerard Pardo and Oscar Rovira (Unit of Diabetes, Endocrinology and Nutrition. Institut d’Investigació Biomèdica de Girona, Hospital Universitari de Girona Dr Josep Trueta). JMM was supported by Sara Borrell fellowship from the Instituto de Salud Carlos III. This work was supported by research grants from the Ministerio de Educación y Ciencia (MEC) (SAF2008-02073 and PI070954), the Instituto de Salud Carlos III (CIBERobn) and Consejería de Salud Junta de Andalucía (PI-0327-2010). JMM was supported by Sara Borrell Fellowship from the Instituto Carlos III. CIBERobn de Fisiopatología de la Obesidad y Nutrición and CIBER de Diabetes y Enfermedades Metabólicas Asociadas are ISCIII projects. Funding was also obtained from the Commission’s Sixth Framework Program (CRESCENDO consortium, integrated project LSHM-CT-2005-018652), ANR GENOPAT (2008-P006850) and INSERM. The French arm of the World Health Organization-MONICA population study was funded by grants from the Conseil Régional du Nord-Pas de Calais, the Caisse Primaire d’Assurance Maladie de Sélestat, the Association Régionale de Cardiologie d’Alsace, ONIVINS, Parke-Davis, the Mutuelle Générale de l’Education Nationale (MGEN), the Réseau National de Santé Publique, the Direction Générale de la Santé, the INSERM, the Institut Pasteur de Lille and the Unité d’Evaluation du Center Hospitalier et Universitaire de Lille, and to the THRA study group for their help in recruitment of subjects (Enrique Gómez-Gracia (University of Málaga, Málaga, Spain), Miguel Fiol (University Institute for Health Sciences Investigation, Palma de Mallorca, Spain), Fernando Arós (Hospital Txagorritxu, Vitoria, Spain), José Lapetra (San Pablo Health Center, Sevilla, Spain), Luis Serra-Majem (Las Palmas University, Las Palmas, Spain, Xavier Pintó (Hospital de Bellvitge, Hospitales de Llobregat, Spain), Carolina Ortega-Azorín and María Arregui (Genetic and Molecular Epidemiology Unit. Department of Preventive Medicine. University of Valencia, Valencia, Spain)).

Author information

Authors and Affiliations

  1. Department of Diabetes, Endocrinology and Nutrition. Institut d’Investigació Biomédica de Girona, Girona, Spain

    J M Fernández-Real, F Ortega & W Ricart

  2. CIBER Fisiopatologia de la Obesidad y la Nutrición, CIBEROBN (CB06/03), Instituto de Salud Carlos III, Girona, Spain

    J M Fernández-Real, D Corella, F Ortega, J Salas-Salvadó, M I Covas, W Ricart, E Ros & R Estruch

  3. Department of Preventive Medicine. University of Valencia, Genetic and Molecular Epidemiology Unit, Valencia, Spain

    D Corella

  4. INSERM, U744; Institut Pasteur de Lille; Univ. Lille Nord de France; UDSL,

    L Goumidi, D Cottel, P Amouyel, A Meirhaeghe & F Soriguer

  5. Institut Pasteur de Lille, Lille, France

    L Goumidi, D Cottel, P Amouyel, A Meirhaeghe & F Soriguer

  6. Joint IRB-BSC program on Computational Biology. Barcelona Supercomputing Center, Barcelona, Catalonia, Spain

    J M Mercader

  7. Servicio de Endocrinología y Nutrición, Hospital Universitario Carlos Haya, Malaga, Spain

    S Valdés, G Rojo Martínez, J M Gómez-Zumaquero, P Botas & E Delgado

  8. CIBER of Diabetes and Metabolism (CIBERDEM) (CB07/08), Instituto de Salud Carlos III, Malaga, Spain

    S Valdés, G Rojo Martínez, J M Gómez-Zumaquero, P Botas & E Delgado

  9. Hospital Central de Asturias, Oviedo, Spain

    S Valdés

  10. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain

    M-T Martinez-Larrad & M Serrano-Rios

  11. Human Nutrition Department, School of Medicine, University Rovira i Virgili, Reus, Spain

    J Salas-Salvadó

  12. Department of Preventive Medicine and Public Health, University of Navarra, Spain

    M A Martinez González

  13. Cardiovascular Risk and Nutrition Research Group, IMIM-Institut de Recerca del Hospital del Mar, Barcelona, Spain

    M I Covas

  14. INSERM, U558, Faculté de Médecine, Université Paul Sabatier, Toulouse, France

    J Ferrieres

  15. Lipid Unit, Service of Endocrinology, Hospital Clinic, Barcelona, Spain

    E Ros

  16. Department of Internal Medicine, Hospital Clinic, IDIB APS, University of Barcelona, Barcelona, Spain

    R Estruch

Authors
  1. J M Fernández-Real
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Corella
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Goumidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J M Mercader
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Valdés
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Rojo Martínez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F Ortega
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M-T Martinez-Larrad
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J M Gómez-Zumaquero
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J Salas-Salvadó
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. M A Martinez González
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M I Covas
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P Botas
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. E Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. D Cottel
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. J Ferrieres
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. P Amouyel
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. W Ricart
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. E Ros
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. A Meirhaeghe
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. M Serrano-Rios
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. F Soriguer
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. R Estruch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J M Fernández-Real.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Author Contributions

RE researched data and contributed to discussion; DC, LG, JMM, SV, GRM, FO, JMG-Z, JS-S, MIC, ER, MS-R, FS researched data; M-TM-L, MAMG, PB, ED, DC, JF, PA, WR, AM: contributed to discussion and JMF-R: researched data and wrote the manuscript.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fernández-Real, J., Corella, D., Goumidi, L. et al. Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene–diet interactions. Int J Obes 37, 1499–1505 (2013). https://doi.org/10.1038/ijo.2013.11

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2013.11

Keywords

This article is cited by

Search

Advanced search

Quick links