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Genetics and Epigenetics

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

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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 m2 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 m2, 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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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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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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