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Genetics and Epigenetics

Genetic variation in the obesity gene FTO is not associated with decreased fat oxidation: the NEO study

International Journal of Obesity volume 41, pages 1594–1600 (2017)Cite this article

Subjects

Abstract

Background:

The fat mass and obesity-associated (FTO) gene harbors the strongest common genetic variant associated with obesity. Recently, rs1421085-T to -C substitution mapped in FTO was shown to induce a developmental shift of human adipocytes from an energy-combusting beige to an energy-storing white phenotype in vitro. As browning of adipocytes selectively enhances fat oxidation (FatOx), we hypothesized that rs1421085-C in FTO is associated with deceased FatOx compared with carbohydrate oxidation (CarbOx) and an increased respiratory quotient (RQ).

Methods:

In the Netherlands Epidemiology of Obesity study, a population-based cohort study of middle-aged individuals (45–65 years), anthropometry and genotyping was performed (n=5744), in addition to indirect calorimetry (n=1246). With linear regression analyses, we examined associations of rs1421085 genotype with FatOx, CarbOx and RQ.

Results:

In the total study population, 36.7% carried the rs1421085-TT genotype, 47.6% rs1421085-CT and 15.7% rs1421085-CC. Mean (s.d.) age was 56 (6) years, mean (s.d.), body mass index (BMI) was 26.3 (4.4) kg m−2 and 56% of the total population were women. Measures of adiposity (difference, 95% confidence interval) were higher in CC carriers compared with that in rs1421085-TT carriers: BMI +0.56 (0.15, 0.98) kg m−2, waist circumference +1.25 (0.02, 2.49) cm and total body fat mass +1.21 (0.28, 2.14) kg. However, no differences in mean FatOx (+2.5 (−2.4, 7.4) mg min−1), CarbOx (−6.1 (−17.4, 5.2) mg min−1) or RQ (−0.01 (−0.02, 0.01)) were observed between the two genotypes.

Conclusions:

We observed no evidence for associations of rs1421085 in FTO with FatOx and RQ. This indicates that the rs1421085-C allele in FTO induces obesity likely via other pathways than via reduced FatOx.

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References

  1. American College of Cardiology/American Heart Association Task Force on Practice Guidelines, Obesity Expert Panel.. Executive summary: Guidelines (2013) for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society published by the Obesity Society and American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Based on a systematic review from the The Obesity Expert Panel, 2013. Obesity (Silver Spring, MD) 2013; 22 (Suppl 2): S5–S39.

    Google Scholar 

  2. Loos RJ, Yeo GS . The bigger picture of FTO: the first GWAS-identified obesity gene. Nat Rev Endocrinol 2014; 10: 51–61.

    Article  CAS  Google Scholar 

  3. Elks CE, den Hoed M, Zhao JH, Sharp SJ, Wareham NJ, Loos RJ et al. Variability in the heritability of body mass index: a systematic review and meta-regression. Front Endocrinol 2012; 3: 29.

    Article  Google Scholar 

  4. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science (New York, NY) 2007; 316: 889–894.

    Article  CAS  Google Scholar 

  5. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet 2007; 3: e115.

    Article  Google Scholar 

  6. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU 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. Fall T, Hagg S, Magi R, Ploner A, Fischer K, Horikoshi M et al. The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis. PLoS Med 2013; 10: e1001474.

    Article  Google Scholar 

  8. Claussnitzer M, Dankel SN, Kim KH, Quon G, Meuleman W, Haugen C et al. FTO obesity variant circuitry and adipocyte browning in humans. N Engl J Med 2015; 373: 895–907.

    Article  CAS  Google Scholar 

  9. Zurlo F, Lillioja S, Esposito-Del Puente A, Nyomba BL, Raz I, Saad MF et al. Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am J Physiol 1990; 259 (Part 1): E650–E657.

    CAS  PubMed  Google Scholar 

  10. Astrup A, Buemann B, Christensen NJ, Toubro S . Failure to increase lipid oxidation in response to increasing dietary fat content in formerly obese women. Am J Physiol 1994; 266 (Part 1): E592–E599.

    CAS  PubMed  Google Scholar 

  11. Raben A, Andersen HB, Christensen NJ, Madsen J, Holst JJ, Astrup A . Evidence for an abnormal postprandial response to a high-fat meal in women predisposed to obesity. Am J Physiol 1994; 267 (Part 1): E549–E559.

    CAS  PubMed  Google Scholar 

  12. Bakker LE, Boon MR, van der Linden RA, Arias-Bouda LP, van Klinken JB, Smit F et al. Brown adipose tissue volume in healthy lean south Asian adults compared with white Caucasians: a prospective, case-controlled observational study. Lancet 2014; 2: 210–217.

    PubMed  Google Scholar 

  13. Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y et al. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013; 123: 3404–3408.

    Article  CAS  Google Scholar 

  14. Arrizabalaga M, Larrarte E, Margareto J, Maldonado-Martin S, Barrenechea L, Labayen I . 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. J Physiol Biochem 2014; 70: 255–262.

    Article  CAS  Google Scholar 

  15. Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN . An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 2008; 359: 2558–2566.

    Article  CAS  Google Scholar 

  16. Haupt A, Thamer C, Staiger H, Tschritter O, Kirchhoff K, Machicao F et al. Variation in the FTO gene influences food intake but not energy expenditure. Exp Clin Endocrinol Diabetes 2009; 117: 194–197.

    Article  CAS  Google Scholar 

  17. Do R, Bailey SD, Desbiens K, Belisle A, Montpetit A, Bouchard C et al. Genetic variants of FTO influence adiposity, insulin sensitivity, leptin levels, and resting metabolic rate in the Quebec Family Study. Diabetes 2008; 57: 1147–1150.

    Article  CAS  Google Scholar 

  18. Berentzen T, Kring SI, Holst C, Zimmermann E, Jess T, Hansen T et al. Lack of association of fatness-related FTO gene variants with energy expenditure or physical activity. J Clin Endocrinol Metab 2008; 93: 2904–2908.

    Article  CAS  Google Scholar 

  19. Speakman JR, Rance KA, Johnstone AM . Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity (Silver Spring, MD) 2008; 16: 1961–1965.

    Article  CAS  Google Scholar 

  20. Berbee JF, Boon MR, Khedoe PP, Bartelt A, Schlein C, Worthmann A et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun 2015; 6: 6356.

    Article  CAS  Google Scholar 

  21. Haman F, Mantha OL, Cheung SS, Ducharme MB, Taber M, Blondin DP et al. Oxidative fuel selection and shivering thermogenesis during a 12 and 24 h cold survival simulation. J Appl Physiol (Bethesda, MD: 1985) 2015; 120: 640–648.

    Article  Google Scholar 

  22. Barquissau V, Beuzelin D, Pisani DF, Beranger GE, Mairal A, Montagner A et al. White-to-brite conversion in human adipocytes promotes metabolic reprogramming towards fatty acid anabolic and catabolic pathways. Mol Metab 2016; 5: 352–365.

    Article  CAS  Google Scholar 

  23. de Mutsert R, den Heijer M, Rabelink TJ, Smit JW, Romijn JA, Jukema JW et al. The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection. Eur J Epidemiol 2013; 28: 513–523.

    Article  Google Scholar 

  24. Livesey G, Elia M . Estimation of energy expenditure, net carbohydrate utilization, and net fat oxidation and synthesis by indirect calorimetry: evaluation of errors with special reference to the detailed composition of fuels. Am J Clin Nutr 1988; 47: 608–628.

    Article  CAS  Google Scholar 

  25. Frayn KN . Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol 1983; 55: 628–634.

    Article  CAS  Google Scholar 

  26. Wendel-Vos GC, Schuit AJ, Saris WH, Kromhout D . Reproducibility and relative validity of the short questionnaire to assess health-enhancing physical activity. J Clin Epidemiol 2003; 56: 1163–1169.

    Article  Google Scholar 

  27. Feunekes GI, Van Staveren WA, De Vries JH, Burema J, Hautvast JG . Relative and biomarker-based validity of a food-frequency questionnaire estimating intake of fats and cholesterol. Am J Clin Nutr 1993; 58: 489–496.

    Article  CAS  Google Scholar 

  28. RIVMNEVO: Dutch Food Composition Database. RIVM, The Netherlands, 2011.

  29. Korn EL, Graubard BI . Epidemiologic studies utilizing surveys: accounting for the sampling design. Am J Public Health 1991; 81: 1166–1173.

    Article  CAS  Google Scholar 

  30. Lumley T Analysis of Complex Survey Samples, 2004. Available at: http://www.jstatsoft.org/v09/i08/paper (last accessed 02 May 2013).

  31. Schilperoort M, Hoeke G, Kooijman S, Rensen PC . Relevance of lipid metabolism for brown fat visualization and quantification. Curr Opin Lipidol 2016; 27: 242–248.

    Article  CAS  Google Scholar 

  32. Wang Z, Heshka S, Gallagher D, Boozer CN, Kotler DP, Heymsfield SB . Resting energy expenditure-fat-free mass relationship: new insights provided by body composition modeling. Am J Physiol 2000; 279: E539–E545.

    CAS  Google Scholar 

  33. Heymsfield SB, Thomas D, Bosy-Westphal A, Shen W, Peterson CM, Muller MJ . Evolving concepts on adjusting human resting energy expenditure measurements for body size. Obes Rev 2012; 13: 1001–1014.

    Article  CAS  Google Scholar 

  34. Heymsfield SB, Gallagher D, Kotler DP, Wang Z, Allison DB, Heshka S . Body-size dependence of resting energy expenditure can be attributed to nonenergetic homogeneity of fat-free mass. Am J Physiol Endocrinol Metab 2002; 282: E132–E138.

    Article  CAS  Google Scholar 

  35. Tacke M, Ebner N, Boschmann M, Jarius A, Valentova M, Fulster S et al. Resting energy expenditure and the effects of muscle wasting in patients with chronic heart failure: results from the Studies Investigating Comorbidities Aggravating Heart Failure (SICA-HF). J Am Med Dir Assoc 2013; 14: 837–841.

    Article  Google Scholar 

  36. Piche T, Schneider SM, Tran A, Benzaken S, Rampal P, Hebuterne X . Resting energy expenditure in chronic hepatitis C. J Hepatol 2000; 33: 623–627.

    Article  CAS  Google Scholar 

  37. Weinsier RL, Hunter GR, Heini AF, Goran MI, Sell SM . The etiology of obesity: relative contribution of metabolic factors, diet, and physical activity. Am J Med 1998; 105: 145–150.

    Article  CAS  Google Scholar 

  38. Speakman JR . The 'Fat Mass and Obesity Related' (FTO) gene: mechanisms of impact on obesity and energy balance. Curr Obes Rep 2015; 4: 73–91.

    Article  Google Scholar 

  39. Corpeleijn E, Petersen L, Holst C, Saris WH, Astrup A, Langin D et al. Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study. Obesity (Silver Spring, MD) 2010; 18: 1369–1377.

    Article  CAS  Google Scholar 

  40. Wishnofsky M . Caloric equivalents of gained or lost weight. Am J Clin Nutr 1958; 6: 542–546.

    Article  CAS  Google Scholar 

  41. Hall KD . What is the required energy deficit per unit weight loss? Int J Obes (2005) 2008; 32: 573–576.

    Article  CAS  Google Scholar 

  42. O'Rahilly S, Coll AP, Yeo GS . FTO obesity variant and adipocyte browning in humans. N Engl J Med 2016; 374: 191.

    PubMed  Google Scholar 

  43. Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 2015; 518: 197–206.

    Article  CAS  Google Scholar 

  44. Branson RD, Johannigman JA . The measurement of energy expenditure. Nutr Clin Pract 2004; 19: 622–636.

    Article  Google Scholar 

  45. Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001; 29: 308–311.

    Article  CAS  Google Scholar 

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Acknowledgements

We express our gratitude to all individuals who participate in the NEO study. We are grateful to all participating general practitioners for inviting eligible participants. We furthermore thank Pat van Beelen and all research nurses for collecting the data, Petra Noordijk and her team for laboratory management and DNA isolation, and Ingeborg de Jonge for all data management of the NEO study. The genotyping in the NEO study was supported by the Centre National de Génotypage (Paris, France), headed by Jean-Francois Deleuze. The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Center and by the Leiden University, Research Profile Area ‘Vascular and Regenerative Medicine’. We also acknowledge the support of the Netherlands Cardiovascular Research Initiative; an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE). PCN Rensen is an established investigator of the Dutch Heart Foundation (2009T038). LL Blauw is supported by a grant from the Board of Directors of the Leiden University Medical Center. D van Heemst was supported by the European Commission-funded project HUMAN (Health-2013-INNVATION-1-602757).

Author contributions

LLB: Study concept and design, analysis and interpretation of data, statistical analysis, drafting of the manuscript; RN: study concept and design, analysis and interpretation of data, statistical analysis, critical revision of the manuscript; ST: study concept and design, critical revision of the manuscript; JFPB: study concept and design, critical revision of the manuscript; FRR: NEO study concept and design, acquisition of data, critical revision of the manuscript; DvH: study concept and design, critical revision of the manuscript; KWvD: study concept and design, critical revision of the manuscript; DOM-K: study concept and design, critical revision of the manuscript; RdM: NEO study concept and design, acquisition of data, study concept and design, analysis and interpretation of data, critical revision of the manuscript; PCNR: study concept and design, analysis and interpretation of data, critical revision of the manuscript, study supervision.

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands

    L L Blauw, J F P Berbée, K W van Dijk & P C N Rensen

  2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    L L Blauw, F R Rosendaal, D O Mook-Kanamori & R de Mutsert

  3. Department of Medicine, Division of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands

    R Noordam, S Trompet & D van Heemst

  4. Department Cardiology, Leiden University Medical Center, Leiden, The Netherlands

    S Trompet

  5. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands

    J F P Berbée, K W van Dijk & P C N Rensen

  6. Department Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

    K W van Dijk

  7. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands

    D O Mook-Kanamori

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  1. L L Blauw
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Correspondence to L L Blauw.

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Blauw, L., Noordam, R., Trompet, S. et al. Genetic variation in the obesity gene FTO is not associated with decreased fat oxidation: the NEO study. Int J Obes 41, 1594–1600 (2017). https://doi.org/10.1038/ijo.2017.146

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