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. Author manuscript; available in PMC: 2014 Mar 17.
Published in final edited form as: Physiol Res. 2010 Oct 15;60(1):175–183. doi: 10.33549/physiolres.932066

FTO variant, energy intake, physical activity and basal metabolic rate in Caucasians. The HAPIEE study

J A HUBACEK a,b,c,*, H PIKHART d, A PEASEY d, M BOBAK d
PMCID: PMC3955871  EMSID: EMS57349  PMID: 20945952

Abstract

The FTO gene variants are the most important genetic determinants of body weight and BMI known so far, but the mechanism of the effect remains unclear. We have analyzed FTO rs17817449 variant (G>T in first intron) in 6,024 adults aged 45-69 years. Dietary intake was calculated from 140-items food frequency questionnaire, physical activity has been assessed using questions on the number of hours spent during a typical week by sport, walking and other activities out of work requiring heavy and medium physical activity and basal metabolic rate was calculated. The FTO variant was significantly associated with basal metabolic rate (Kcal per day and kg of body weight) in females (P = 0.006; GG = 19.3 ± 2.2, GT = 19.5 ± 2.2, TT = 19.7 ± 2.2), but not in males (P = 0.42, GG = 20.9 ± 1.9, GT = 21.0 ± 1.8, TT = 21.1 ± 1.8). Total energy intake, total energy intake in fat, in carbohydrates, in proteins and in alcohol, and performed physical activity were not associated with FTO genotype either in males or females.

We conclude that effect of the FTO rs17817449 variant on BMI values in adults is not mediated through the association with energy intake or physical activity, but rather through the effect on basal metabolic rate, and that this effect is more pronounced in females.

Keywords: FTO, polymorphism, body mass index, energy expenditure, physical activity, basal metabolic rate

Introduction

Obesity is between the major health problems in recent years, and obesity prevalence increased dramatically over the last decades. It is estimated, that just one third of the population in the most affected countries has a normal (18 - 25 kg/m2) body mass index (BMI).

Generally, obesity results from the interactions between unhealthy life style (abundant energy intake and low physical activity) and genetic predispositions, although some other factors such as non-exercise activity thermogenesis, sleeping behaviour, higher inside temperature comfort, or different environmental chemicals and psychosocial factors play also an important role (Hubacek 2009, Adámková et al. 2009).

The level of involvement of genetic factors on obesity is estimated to be 40 – 60% (Wardle et al. 2008, Hainer et al. 2008). Recently, many new genes associated with obesity have been identified using genome wide association studies (for example see Thorleifsson et al. 2009).

Among the newly detected genes, particular interest is focused on the FTO gene, the first locus unequivocally associated with BMI values. FTO (“fat mass and obesity related”, gene ID 79068, OMIM accession number 610966) gene (and its SNPs) was simultaneously detected by several research groups as a significant predictor of body mass index (Dina et al. 2007, Frayling et al. 2007, Tönjes et al. 2010). FTO variants are associated with BMI in a wide range of populations and the effect is not restricted just to Caucasians (Dina et al. 2007, Frayling et al. 2007, Hunt et al. 2008, Hubacek et al. 2008, Hubacek et al. 2009) but, despite the less homogeneity, FTO affects BMI also in Asian (Ohashi et al. 2007, Tan et al. 2008) and African populations (Hennig et al. 2009, Liu et al. 2010).

FTO is widely expressed in almost all tissue, but the exact role of the FTO is unknown – it was described, that the FTO exhibits slight DNA demethylase (Gerken et al. 2007) and non-heme dioxygenase activities (Sanchez-Pulido and Andrade-Navarro, 2007), but no direct function in energy homeostasis was detected and described. It has been shown that Fto knock-out mice develop postnatal growth retardation with a significant reduction of adipose tissue. The extreme leanness of Fto knock-out mice was a consequence of increased energy expenditure (despite the decreased activity of the animals and increased energy intake (Fischer et al. 2009). In humans, papers about potential impacts of FTO variants on dietary intake and/or energy expenditure are inconsistent and the inconsistency is in some cases caused by a insufficient number of analyzed individuals and low power of the studies (Speakman et al. 2008, Cecil et al. 2008, Berentzen et al. 2008, Timpson et al. 2008, Johnson et al. 2009, Hakanen et al. 2009, Haupt et al. 2009, Liu et al. 2010, Hasselbalch et al. 2010).

We have examined the hypothesis that BMI associated FTO variant is related to elevated energy intake, lower physical activity performed or with basal metabolic rate on a large population sample of middle-aged adults.

Material and Methods

Subjects

The examined individuals come from the Czech part of the HAPIEE (Health, Alcohol and Psychosocial factors In Eastern Europe) project, which examined random samples of men and women aged 45-69 years in seven Czech towns: Jihlava, Havirov, Hradec Kralove, Karvina, Kromeriz, Liberec and Usti nad Labem. Details of the study have been described elsewhere (Peasey et al. 2006). Briefly, participants - 8, 856 individuals recruited (response rate 55%), 6 681 (3, 079 males and 3, 602 females) with DNA samples available, completed an extensive questionnaire on medical history, health status, life style, diet and socioeconomic and psychosocial factors, underwent a short examination, including anthropometry, and provided a blood sample. After validation of the dietary intake information (Boylan et al. 2009), 6, 024 individuals with complete data on all required variables were statistically analyzed in details. The study was approved by the local ethics committees at both Czech National Institute of Public health and University College London.

Genetic analysis

DNA was extracted using salting out method (Miller et al. 1988), and FTO SNP rs17817449 was genotyped using PCR - RFLP as described elsewhere (Hubacek et al. 2008). To ensure accuracy of genotyping, one plate (containing 94 DNA samples) was analyzed twice within one week with 100% conformity. Call rate for genotyping was 96%.

Dietary intake and BMR

Dietary intake was assessed by a 140-item food frequency questionnaire (FFQ) (Willett et al. 1985, Brunner et al. 2001). The intake of total energy, fats, carbohydrates, proteins and alcohol is estimated from the FFQ, using the McCance and Widdowson’s The Composition of Foods (Food Standards Agency, 2002) and correcting for major differences in composition of principal foods and local foods and recipes (Boylan et al. 2009). Basal metabolic rate was calculated according Schofield (1985).

Physical activity

Physical activity has been assessed using questions on the number of hours spent by participants during a typical week in sports, walking and other activities outside of work requiring heavy or medium physical activity (2 questions). The potential confounding effect of physical disability was taken into account using the physical functioning module of the SF-36 questionnaire (Wagner et al. 1998).

Statistical analyses

Deviation of genotypes distributions from Hardy-Weinberg equilibrium were analyzed using the chi-square test (http://www.tufts.edu/~mcourt01/Documents/Court%20lab%20%20HW%20calculator.xls). One-way analysis of variance in STATA statistical software (version 9; College Station, TX) was used for statistical analyses comparing dietary intake, BMR and physical activity between individuals with different genotypes. Mean ± SD are reported for each exposure and genotype group, and P-values less than 0.05 were considered to be significant.

Results

Study subjects

The basic characteristics of the groups under study are summarized in Table 1. The distribution of individual genotypes is within Hardy-Weinberg equilibrium and is similar to the neighbouring European samples reported previously (Dina et al. 2007, Frayling et al. 2007).

Table 1.

Baseline characteristics for analyzed individuals (N = 6, 024)

HAPIEE HAPIEE males HAPIEE females
N 6, 024 2, 780 3, 244
Age (years) 58.1 ± 6.9 58.5 ± 6.9 57.7 ± 6.9
BMI (kg/m2) 28.2 ± 4.6 28.2 ± 3.9 28.1 ± 5.1
WHR 0.885 ± 0.085 0.944 ± 0.059 0.834 ± 0.069
Diabetes 657 (10.9%) 359 (12.9%) 298 (9.2%)
Current smoking 1531 (25.7%) 793 (28.8%) 738 (23.0%)
Total energy intake 2038 ± 710 2103 ±705 1982 ±709
 Total fat energy intake 742 ± 299 772 ± 308 717 ±289
 Total carbohydrate energy intake 886 ± 353 868 ± 330 901 ±372
 Total protein energy intake 354 ± 130 369 ±134 342 ±126
 Total energy intake in alcohol 60 ± 99 101 ±125 26 ± 49
Physical activity (h/week)* 4.4 ± 5.3 4.4 ± 5.4 4.4 ± 5.2
Basal metabolic rate 1587 ±237 1794 ±164 1412 ± 118
BMR/1kg of body weight 20.21 ± 2.18 21.01 ± 1.85 19.54 ± 2.21
Open in a new tab
*

h/week in sports/games/walking/Viking

Data are given like numbers / percents or mean ± SD.

Energy intakes are in Kcal/Day.

The total energy intake per day was higher in males than in females (2103 ± 705 Kcal vs 1982 ± 709 Kcal) and this difference was caused generally by higher fat and ethanol intake in males (Tab 1), hours of physical activity were the same in males and females and, as expected, basal metabolic rate and basal metabolic rate per kg of body weight were also higher in males.

Consistently with the results described in original articles (Dina et al. 2007, Frayling et al. 2007, for reviewed see Fawcett and Barroso 2010) rs17817449 G allele was significantly associated with obesity related phenotype (BMI) in a total combined sample (P = 0.0001) as we have described before (Hubacek et al. 2008) and the presence of the G allele increase the BMI in linear trend both in males (P < 0.005) and females (P < 0.001). There were no significant associations of the FTO gene SNP with waist-hip ratio.

Association between FTO SNP and energy intake, physical activity and basal metabolic rate

Associations between FTO genotype and variables of interest are summarized in Table 2. FTO SNP rs17817449 was not associated with the mean values of the total energy intake. Similarly, total fat, carbohydrates, protein and alcohol energy intakes are independent on FTO genotypes in entire population or in males or females, if analyzed separately.

Table 2.

Association between FTO rs17817449 variant, energy intake, physical activity and basal metabolic rate in HAPIEE Slavic Czech population

FTO P-value
GG GT TT
N 1, 157 2, 886 1, 981
ENTIRE POPULATION
Total energy intake 2050 ±712 2031 ±702 2040 ± 721 0.75
 Total fat energy intake 753 ± 300 739 ± 298 740 ± 301 0.38
 Total carbohydrate energy intake 886 ± 352 881 ± 347 892 ± 363 0.59
 Total protein energy intake 357 ± 13 355 ±130 352 ±131 0.61
 Total energy intake in alcohol 59 ± 101 61 ± 101 60 ± 96 0.82
Physical activity* 4.3 ± 5.1 4.4 ± 5.3 4.4 ± 5.4 0.94
Basal metabolic rate (BMR) 1603 ±243 1588 ±235 1576±236 0.008
BMR/1kg of body weight 20.09 ± 2.20 20.21 ± 2.16 20.30 ± 2.18 0.03
MALES
Total energy intake 2078 ± 697 2104 ±698 2117 ±722 0.60
 Total fat energy intake 771 ±303 774 ±312 769 ± 305 0.94
 Total carbohydrate energy intake 855±314 865 ± 322 880 ± 352 0.34
 Total protein energy intake 363±131 370 ±135 371 ±136 0.49
 Total energy intake in alcohol 98 ± 128 101 ±126 103 ±121 0.73
Physical activity* 4.3 ± 5.2 4.4 ± 5.5 4.3 ± 5.4 0.79
Basal metabolic rate 1808 ±169 1792 ±161 1788±163 0.08
BMR/1kg of body weight 20.92 ± 1.91 21.01 ± 1.84 21.06 ± 1.83 0.42
FEMALES
Total energy intake 2024 ± 724 1968 ±700 1977 ±714 0.25
 Total fat energy intake 738 ± 297 709 ± 281 716 ±296 0.12
 Total carbohydrate energy intake 914±381 895 ± 368 901 ±371 0.56
 Total protein energy intake 352 ±129 341 ±125 337 ±125 0.07
 Total energy intake in alcohol 24 ± 44 26 ± 51 26 ± 48 0.54
Physical activity* 4.4 ± 5.0 4.4 ± 5.2 4.4 ± 5.4 0.99
Basal metabolic rate 1419 ± 121 1414 ±120 1404 ± 113 0.02
BMR/1kg of body weight 19.33 ± 2.17 19.52 ± 2.19 19.69 ± 2.25 0.006
Open in a new tab
*

h/week in sports/games/walking/Viking

Data are given like numbers / percents or mean ± SD

Energy intakes are in Kcal/Day

Basal metabolic rate was higher in GG homozygotes (P = 0.008) and the effect is more visible in females (P = 0.02) than in males (P = 0.08). However and more importantly, the basal metabolic rate per kilogram of body height was highest in carriers of the TT genotype, in females (P = 0.006) but not in males (P = 0.42).

Discussion

This study provides the first evidence for an association between the FTO gene variant and basal metabolic rate per kilogram of body weight in Caucasian adults. Carriers of the GG genotype (rs 17817449), which is associated with elevated BMI, have slightly lower basal metabolic rate per kilogram of body weight than others and this association was significant in females and in males the similar, but not significant trend was visible.

Our results are in contrast with the study performed by Speakman and colleagues (2008) who did not find a significant association between FTO and basal metabolic rate, however, they include 150 individuals only and the study is clearly underpowered to detect the effect which is according to our study, expected to be just about 20-25 Kcal/kg/day between homozygotes.

The FTO gene variants were primarily described to be associated with BMI values in Caucasians studies. The gene for the FTO codes for the protein with enzymatic activities that does not seem to have a direct effect on energy management (and the described activities are detectable, but low). Data about the possible association of the FTO gene variants with the preference of energy dense food, higher fat intake or markers of physical activity are inconsistent, and the exact mechanism of the effect of FTO on higher BMI/obesity development remains elusive.

Namely, the lack of the association between energy intake and physical activity performed in our study is in agreement with the previous findings of Hakanen et al. (2009) who did not find an association between energy intake and physical activity at age 15, with data from Liu et al. (2010) who failed to detect an association between energy intake and physical activity in almost two thousands adults and also large study of 756 twin (Hasselbalch et al. 2010) pairs failed to associate FTO variant with energy intake or physical activity. Dietary energy intake was also not associated with FTO variant in a group of about 2300 prepubertal children (Johnson et al. 2009). Finally, Berentzen et al. (2008) did not detect an association between energy expenditure or energy intake and FTO genotypes.

In contrast, the obesity associated allele was associated with increased energy intake (but not with the weight of food ingested) in a small sample of 97 children (Cecil et al. 2008), in 150 Germans who underwent an lifestyle intervention program (Haupt et al. 2009), and finally, on much larger group of 3500 children, Timpson et al. (2008) have observed a significant effect of FTO variant on the both total energy and fat daily energy intake. FTO obesity genotype was also in children associated with lower satiety responsiveness and elevated enjoyment of food (Wardle et al. 2008). Slight effect on resting metabolic rate was suggested in the Quebeck Family study (Do et al. 2008), however, higher RMR was observed in association with obesity associated genotype and disappear after adjustment for fat composition.

Generally, it can be concluded, that the effect of FTO alleles on physical activity performed was not detected and the effect on dietary energy intake, if any, is detectable just in prepubertal and pubertal children, but not in adults. Despite the fact, that not in all studies were analyzed the same SNPs, it is unlikely, that this fact will explain the obtained discrepancies – all variants have been associated with mean BMI in similar ways and all SNPs within the FTO first intron locus are in almost complete linkage disequilibrium.

Thus so far, despite there is another suggested mechanism (higher lipolysis, Wåhlén et al. 2008) how the FTO could affect body weight, the real and exact effect remains unknown. It can not be excluded, that in fact the variants within the first introns of FTO are in strong linkage disequilibrium not just with each other, but also with variants in neighboring genes – for example, the gene for retinitis pigmentosa GTPase regulator-interacting protein like 1 was suggested (Fawcet and Barroso 2010) despite the fact, that also the association of this gene with energy metabolism is more than speculative. It must be considered that the some inaccuracy in self reported dietary intake may play a role. Despite detailed control it is known, that self reported dietary intake assessment is burdened by inaccuracies arising from the underestimation (Schoeller 1995). However, it is hard to believe, that such underestimation will be different between carriers of different FTO genotypes and despite the fact, that obese individuals are more prone to such underestimation (Westerterp and Goris 2002), the real BMI differences between individuals with different FTO genotypes are not so high.

In conclusion, our study confirms the previous finding that the FTO genotype is not associated with energy intake or performed physically activity in adults but, we have detected that it may have an effect on basal metabolic rate per kilogram of body weight. This effect was more prone in females than in males. Confounding may play role in this finding. According to our data, males performing higher physical activity have higher energy intake than males with low physical activity, but this association was not found for females – they have the same energy intake regardless of physical activities performed. Further analysis is needed to investigate whether the effect of FTO variants on basal metabolic rate per kilogram of body weight is sufficient to cause expected mean differences in body weight (estimated to be almost 2 kg per one risky allele).

Acknowledgements

This project was supported by grants from IKEM, CR, (project no. 00023001) by MEYS CR (project No. 1M0510), by the Welcome Trust, UK and by the US national Institute Aging.

Abbreviations

BMI

body mass index

CR

call rate

FTO

fat mass and obesity related

MAF

minor allele frequency

SNP

single nucleotide polymorphisms

WHR

waist hip ratio

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