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Lack of Association of Fatness-Related FTO Gene Variants with Energy Expenditure or Physical Activity

Institute of Preventive Medicine (T.B., S.I.I.K., C.H., E.Z., T.J., T.I.A.S.), Copenhagen University Hospitals, Centre for Health and Society, DK-1357 Copenhagen, Denmark; Center for Pharmacogenomics (S.I.I.K.), the Panum Institute, DK-2200 Copenhagen, Denmark, and Department of Human Nutrition (A.A.), Faculty of Life Sciences, University of Copenhagen, DK-1958 Fredericksburg, Denmark; Steno Diabetes Centre (T.H., O.P.), DK-2820 Gentofte, Denmark; Faculty of Health Science (O.P.), University of Aarhus, DK-8000 Aarhus, Denmark; and Reduce-Research Clinic of Nutrition (S.T.), Hvidovre University Hospital, DK-2650 Hvidovre, Denmark

Address all correspondence and requests for reprints to: Tina Berentzen, Institute of Preventive Medicine, Øster Søgade 18, Copenhagen K, DK-1357, Denmark. E-mail: tb{at}ipm.regionh.dk.

Context: A common variant in the first intron of FTO (rs9939609, T/A) is associated with fatness in Caucasians.

Objective: FTO may regulate energy homeostasis through the hypothalamus, and we hypothesized that AA-genotypes of rs9939609 FTO have lower energy expenditure and/or a lower level of physical activity.

Methods: The study population included all obese young men (body mass index 31 kg/m²) at the mandatory draft board examinations in the Copenhagen area from 1943 to 1977 and a randomly selected control group from this population. Subgroups of 234 obese and 323 controls were examined in 1998–2000 (median age 48 yr). Fat mass (FM), lean body mass (LBM), leisure-time physical activity (LTPA), maximum oxygen uptake (VO₂max), resting energy expenditure (REE), and glucose-induced thermogenesis (GIT) were measured. The FTO rs9939609 variant was genotyped. A recessive transmission mode fit the data best. Logistic regression was used to assess the odds ratios of the AA-genotype in relation to LTPA, VO₂max, REE, and GIT.

Results: The AA-genotype of FTO rs9939609 had higher REE in the age-adjusted model, but the association was eliminated when adjusting for FM and LBM. The AA-genotype was not associated with LTPA, VO₂max, or GIT. This was not influenced by adjustment for age, FM, or LBM. The AA-genotype had increased FM, even with adjustment for age, LBM, REE, GIT, VO₂max, and LTPA. Results were similar for FTO rs8050136 and rs7193144.

Conclusions: Homozygous carriers of the A-allele of rs9939609 FTO do not have lower REE, GIT, VO₂max, or LTPA but higher FM, irrespective of LBM, REE, GIT, VO₂max, and LTPA.