Journal of Physiology and Biochemistry

, Volume 70, Issue 1, pp 255–262

Preliminary findings on the influence of FTO rs9939609 and MC4R rs17782313 polymorphisms on resting energy expenditure, leptin and thyrotropin levels in obese non-morbid premenopausal women

  • María Arrizabalaga
  • Eider Larrarte
  • Javier Margareto
  • Sara Maldonado-Martín
  • Lurdes Barrenechea
  • Idoia Labayen
Original Paper

Abstract

Given that leptin, ghrelin and thyrotropin play a major role in the regulation of resting energy expenditure (REE) and that the FTO rs9939609 and the MC4R rs17782313 polymorphisms have been proposed to affect energy homeostasis, we hypothesized that both polymorphisms are associated with REE and that these relationships can be mediated by leptin, ghrelin and thyrotropin in obesity. Therefore, the present study aimed to examine the relationships between FTO rs9939609 and the MC4R rs17782313 with REE, leptin, ghrelin and thyrotropin levels in obese women. The study comprised 77 obese (body mass index 34.0 ± 2.8 kg/m2) women (age 36.7 ± 7 years). We measured body composition by dual-energy X-ray absorptiometry and REE by indirect calorimetry. We analysed fasting leptin, ghrelin and thyrotropin levels and the ratio of leptin to fat mass was calculated. Genotype distributions of the polymorphisms did not deviate from Hardy–Weinberg expectations (P values >0.2). Women carrying the A allele of the FTO rs9939609 had lower REE (1,580 ± 22 vs. 1,739 ± 35 kcal/day, P < 0.001) and higher leptin to fat mass ratio (1.33 ± 0.05 vs. 1.13 ± 0.08 ng/ml kg, P < 0.05) and thyrotropin levels (1.93 ± 0.10 vs. 1.53 ± 0.16 μU/ml, P < 0.05) regardless of age and body mass index. We found no significant influence of the MC4R rs17782313 on energy metabolism or biochemical variables. Our findings confirm that the A allele of the FTO rs9939609 is associated with lower REE and increased plasma leptin levels. We also found an association between the FTO rs9939609 and thyrotropin, suggesting the possible influence of FTO in the hypothalamic–pituitary–thyroid axis as a potential mechanism of the increased adiposity.

Keywords

FTO rs9939609 MC4R rs17782313 Resting energy expenditure Leptin Thyrotropin Obesity 

References

  1. 1.
    al-Adsani H, Hoffer LJ, Silva JE (1997) Resting energy expenditure is sensitive to small dose changes in patients on chronic thyroid hormone replacement. J Clin Endocrinol Metab 82:1118–1125PubMedGoogle Scholar
  2. 2.
    Andreasen CH, Stender-Petersen KL, Mogensen MS, Torekov SS, Wegner L, Andersen G et al (2008) Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 57:95–101PubMedCrossRefGoogle Scholar
  3. 3.
    Berentzen T, Kring SI, Holst C, Zimmermann E, Jess T, Hansen T, Pedersen O, Toubro S, Astrup A, Sørensen TI (2008) Lack of association of fatness-related FTO gene variants with energy expenditure or physical activity. J Clin Endocrinol Metab 93:2904–2908PubMedCrossRefGoogle Scholar
  4. 4.
    Biondi B (2010) Thyroid and obesity: an intriguing relationship. In J Clin Endocrinol Metab 95:3614–3617CrossRefGoogle Scholar
  5. 5.
    Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN (2008) An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 359:2558–2566PubMedCrossRefGoogle Scholar
  6. 6.
    Cole SA, Butte NF, Voruganti VS, Cai G, Haack K, Kent JW Jr, Blangero J, Comuzzie AG, McPherson JD, Gibbs RA (2010) Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children. Am J Clin Nutr 91:191–199PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Compher C, Frankenfield D, Keim N, Roth-Yousey L (2006) Best practice methods to apply to measurement of resting metabolic rate in adults: a systematic review. J Am Diet Assoc 106:881–903PubMedCrossRefGoogle Scholar
  8. 8.
    Cooper JA, Watras AC, O’Brien MJ, Luke A, Dobratz JR, Earthman CP, Schoeller DA (2009) Assessing validity and reliability of resting metabolic rate in six gas analysis systems. J Am Diet Assoc 109:128–132PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C, Pérusse L, Vohl MC, Engert JC (2008) Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec family study. Diabetes 57:1147–1150PubMedCrossRefGoogle Scholar
  10. 10.
    Doucet E, St Pierre S, Alméras N, Mauriège P, Richard D, Tremblay A (2000) Changes in energy expenditure and substrate oxidation resulting from weight loss in obese men and women: is there an important contribution of leptin? J Clin Endocrinol Metab 85:1550–1556PubMedGoogle Scholar
  11. 11.
    Dougkas A, Yaqoob P, Givens DI, Reynolds CK, Minihane AM (2013) The impact of obesity-related SNP on appetite and energy intake. Br J Nutr 22:1–6Google Scholar
  12. 12.
    Dwivedi OP, Tabassum R, Chauhan G, Ghosh S, Marwaha RK, Tandon N, Bharadwaj D (2012) Common variants of FTO are associated with childhood obesity in a cross-sectional study of 3,126 urban Indian children. PLoS One 7:e47772PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Fang H, Li Y, Du S, Hu X, Zhang Q, Liu A, Ma G (2010) Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children. BMC Med Genet 11:136PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Feldt-Rasmussen U (2007) Thyroid and leptin. Thyroid 17:413–419PubMedCrossRefGoogle Scholar
  15. 15.
    Fischer J, Koch L, Emmerling C, Vierkotten J, Peters T, Brüning JC, Rüther U (2009) Inactivation of the Fto gene protects from obesity. Nature 458:894–898PubMedCrossRefGoogle Scholar
  16. 16.
    Frayling TM, Timpson NJ, Weedon MN et al (2007) A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316:889–894PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Gil-Campos M, Aguilera CM, Cañete R, Gil A (2006) Ghrelin: a hormone regulating food intake and energy homeostasis. Br J Nutr 96:201–226PubMedCrossRefGoogle Scholar
  18. 18.
    Hakanen M, Raitakari OT, Lehtimäki T, Peltonen N, Pahkala K, Sillanmäki L, Lagström H, Viikari J, Simell O, Rönnemaa T (2009) FTO genotype is associated with body mass index after the age of seven years but not with energy intake or leisure-time physical activity. J Clin Endocrinol Metab 94:1281–1287PubMedCrossRefGoogle Scholar
  19. 19.
    Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F, Häring HU, Stefan N, Fritsche A (2009) Variation in the FTO gene influences food intake but not energy expenditure. Exp Clin Endocrinol Diabetes 117:194–197PubMedCrossRefGoogle Scholar
  20. 20.
    Knudsen N, Laurberg P, Rasmussen LB, Bülow I, Perrild H, Ovesen L, Jørgensen T (2005) Small differences in thyroid function may be important for body mass index and the occurrence of obesity in the population. J Clin Endocrinol Metab 90:4019–4024PubMedCrossRefGoogle Scholar
  21. 21.
    Krakoff J, Ma L, Kobes S, Knowler WC, Hanson RL, Bogardus C, Baier LJ (2008) Lower metabolic rate in individuals heterozygous for either a frameshift or a functional missense MC4R variant. Diabetes 57:3267–3272PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Kring SI, Holst C, Toubro S, Astrup A, Hansen T, Pedersen O, Sørensen TI (2010) Common variants near MC4R in relation to body fat, body fat distribution, metabolic traits and energy expenditure. Int J Obes (Lond) 34:182–189CrossRefGoogle Scholar
  23. 23.
    Labayen I, Díez N, González A, Parra D, Martínez JA (2003) Effects of protein vs. carbohydrate-rich diets on fuel utilisation in obese women during weight loss. Forum Nutr 56:168–170PubMedGoogle Scholar
  24. 24.
    Labayen I, Díez N, Parra D, González A, Martínez JA (2004) Basal and postprandial substrate oxidation rates in obese women receiving two test meals with different protein content. Clin Nutr 23:571–578PubMedCrossRefGoogle Scholar
  25. 25.
    Labayen I, Forga L, Martinez JA (1999) Nutrient oxidation and metabolic rate as affected by meals containing different proportions of carbohydrate and fat, in healthy young women. Eur J Nutr 38:158–166PubMedCrossRefGoogle Scholar
  26. 26.
    Labayen I, Ortega FB, Ruiz JR, Lasa A, Simón E, Margareto J (2011) Role of baseline leptin and ghrelin levels on body weight and fat mass changes after an energy-restricted diet intervention in obese women: effects on energy metabolism. J Cli Endocrinol Metab 96:E996–E1000CrossRefGoogle Scholar
  27. 27.
    Labayen I, Ruiz JR, Ortega FB, Dallongeville J, Jiménez-Pavón D, Castillo MJ, De Henauw S, González-Gross M, Bueno G, Molnar D, Kafatos A, Díaz LE, Meirhaeghe A, Moreno LA (2011) Association between the FTO rs9939609 polymorphism and leptin in European adolescents: a possible link with energy balance control. The HELENA study. Int J Obes 35:882–882CrossRefGoogle Scholar
  28. 28.
    Larder R, Cheung MK, Tung YC, Yeo GS, Coll AP (2011) Where to go with FTO? Trends Endocrinol Metab 22:53–59PubMedCrossRefGoogle Scholar
  29. 29.
    Liu G, Zhu H, Lagou V, Gutin B, Stallmann-Jorgensen IS, Treiber FA, Dong Y, Snieder H (2010) FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth. BMC Med Genet 11:57PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I et al (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat Genet 40:768–775PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Mejía-Benítez A, Klünder-Klünder M, Yengo L, Meyre D, Aradillas C, Cruz E, Pérez-Luque E, Malacara JM, Garay ME, Peralta-Romero J, Flores-Huerta S, García-Mena J, Froguel P, Cruz M, Bonnefond A (2013) Analysis of the contribution of FTO, NPC1, ENPP1, NEGR1, GNPDA2 and MC4R genes to obesity in Mexican children. BMC Med Genet 14:21PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Nogueiras R, Tschop MH, Zigman JM (2008) Central nervous system regulation of energy metabolism: ghrelin versus leptin. Ann N Y Acad Sci 1126:14–19PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Olszewski PK, Fredriksson R, Eriksson JD, Mitra A, Radomska KJ, Gosnell BA, Solvang MN, Levine AS, Schiöth HB (2009) Hypothalamic FTO is associated with the regulation of energy intake not feeding reward. BMC Neurosci 10:129PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Qi L, Kang K, Zhang C, van Dam RM, Kraft P, Hunter D, Lee CH, Hu FB (2008) Fat mass-and obesity-associated (FTO) gene variant is associated with obesity: longitudinal analyses in two cohort studies and functional test. Diabetes 57:3145–3151PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Reinehr T (2010) Obesity and thyroid function. Mol Cell Endocrinol 316:165–171PubMedCrossRefGoogle Scholar
  36. 36.
    Roef G, Lapauw B, Goemaere S, Zmierczak HG, Toye K, Kaufman JM, Taes Y (2012) Body composition and metabolic parameters are associated with variation in thyroid hormone levels among euthyroid young men. Eur J Endocrinol 167:719–726PubMedCrossRefGoogle Scholar
  37. 37.
    Ruiz JR, Labayen I, Ortega FB, Legry V, Moreno LA, Dallongeville J, Martínez-Gómez D, Bokor S, Manios Y, Ciarapica D, Gottrand F, De Henauw S, Molnár D, Sjöström M, Meirhaeghe A (2010) Attenuation of the effect of the FTO rs9939609 polymorphism on total and central body fat by physical activity in adolescents: the HELENA study. Arch Pediatr Adolesc Med 164:328–333PubMedCrossRefGoogle Scholar
  38. 38.
    Ruiz JR, Larrarte E, Margareto J, Ares R, Alkorta P, Labayen I (2011) Preliminary findings on the role of PLIN1 polymorphisms on body composition and energy metabolism response to energy restriction in obese women. Br J Nutr 106:486–490PubMedCrossRefGoogle Scholar
  39. 39.
    Speakman JR, Rance KA, Johnstone AM (2008) Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring) 16:1961–1965CrossRefGoogle Scholar
  40. 40.
    St-Pierre DH, Karelis AD, Cianflone K, Conus F, Mignault D, Rabasa-Lhoret R, St-Onge M, Tremblay-Lebeau A, Poehlman ET (2004) Relationship between ghrelin and energy expenditure in healthy young women. J Clin Endocrinol Metab 89:5993–5997PubMedCrossRefGoogle Scholar
  41. 41.
    Tews D, Fischer-Posovszky P, Fromme T, Klingenspor M, Fischer J, Rüther U, Marienfeld R, Barth T, Möller P, Debatin K, Wabitsch M (2013) FTO deficiency induces UCP-1 expression and mitochondrial uncoupling in adipocytes. Endocrinology 154:3141–3151PubMedCrossRefGoogle Scholar
  42. 42.
    Thearle MS, Muller YL, Hanson RL, Mullins M, Abdussamad M, Tran J, Knowler WC, Bogardus C, Krakoff J, Baier LJ (2012) Greater impact of melanocortin-4 receptor deficiency on rates of growth and risk of type 2 diabetes during childhood compared with adulthood in Pima Indians. Diabetes 61:250–257PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Xi B, Chandak GR, Shen Y, Wang Q, Zhou D (2012) Association between common polymorphism near the MC4R gene and obesity risk: a systematic review and meta-analysis. PLoS One 7:e45731PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© University of Navarra 2013

Authors and Affiliations

  • María Arrizabalaga
    • 1
  • Eider Larrarte
    • 2
  • Javier Margareto
    • 3
  • Sara Maldonado-Martín
    • 4
  • Lurdes Barrenechea
    • 5
  • Idoia Labayen
    • 1
  1. 1.Department of Nutrition and Food ScienceUniversity of the Basque Country, UPV/EHUVitoriaSpain
  2. 2.Health and Quality of Life Area, TecnaliaMiñanoSpain
  3. 3.Biomedical Research Area, TecnaliaMiñanoSpain
  4. 4.Department of Physical Education and SportUniversity of the Basque Country, UPV/EHUVitoriaSpain
  5. 5.Department of MedicineUniversity of the Basque Country, UPV/EHUVitoriaSpain

Personalised recommendations