Assessment of the FTO gene polymorphisms (rs1421085, rs17817449 and rs9939609) in exercise-trained men and women: the effects of a 4-week hypocaloric diet

There are several single nucleotide polymorphisms (SNPs) on the fat mass and obesity-associated (FTO) gene that are associated with obesity in adults and children [1‐7]. For the FTO SNP rs8050136, homozygotes for the risk allele (A/A) have 1.67 times greater risk of obesity than those who do not have the allele [8]. Furthermore, the FTO genotype was associated with changes in body composition as a result of regular exercise. Thus, carriers of the C allele showed three times greater fat mass and percent body fat losses than the A/A homozygotes [8]. It is unclear if the FTO genotype has an interaction with macronutrient intake. One group tested the effects of an FTO variant (rs1558902) on weight loss in response to 2-year diet interventions. This study demonstrated that a high-protein diet might be beneficial for weight loss and improvement of body composition and fat distribution in individuals with the risk allele of the FTO variant rs1558902 [9]. In an investigation that was comprised of 788 unrelated Mexican-Mestizo individuals, the FTO SNPs (rs9939609, rs1421085, and rs17817449) were a major risk factor for obesity [10]. Recent data characterized the FTO SNP (rs1421085), which results in a T to C nucleotide substitution, in a cohort of exercise-trained men and women [11]. The study population of 108 exercise-trained individuals included professional mixed martial arts fighters, competitive distance runners, collegiate swimmers, stand-up paddlers as well as a cohort of recreational bodybuilders. The data showed that C allele carriers had significantly higher fat mass and percent body fat relative to the TT group. However, due to the cross-sectional nature of this investigation, it was not possible to determine causality regarding the FTO gene and body composition [11]. Nonetheless, it is evident that investigations of the FTO gene focus primarily on overweight or obese individuals [3, 5, 12, 13]. The current investigation is a follow up on the cross-sectional data previously obtained from a cohort of exercise-trained individuals [11]. Certainly, the cross-sectional data shows that the presence of the risk variant for the FTO gene is associated with an elevated fat mass. However, one cannot assign causality based on observational data. Thus, the purpose of this investigation was to determine if body composition was differentially altered in a group of exercise-trained men and women based on their FTO genotype. This is the first investigation in exercise-trained men and women that have examine the role of the FTO SNPs as it relates to caloric restriction and body composition assessment. The FTO SNPs (rs9939609, rs1421085, and rs17817449) were analyzed due to their strong linkage disequilibrium (i.e., there is a non-random association of allele types in these SNPs).

Of the 73 initial subjects that volunteered for the investigation, 10 dropped out (i.e., did not show up for post-testing) and 16 were non-compliant (i.e., did not decrease energy intake). Of the 47 compliant subjects, 15 were of normal risk for obesity whereas 32 were carriers of the risk alleles for the FTO gene (Tables 1, 2 and 3). The HWE test for rs17817449 was χ2 = 0.03, p = 0.86 and rs9939609 was χ2 = 0.81, p = 0.37, suggesting that the population is consistent with Hardy-Weinberg Equilibrium. The HWE test for rs1421085 was χ2 = 4.02, p = 0.04. This was due to a higher number of observed vs. expected heterozygotes (29 vs. 22). Subjects were grouped based on their genotype. Both groups decreased total energy intake significantly (~ 400 kcal) with no difference between groups (Table 4). The decrease in energy intake was due to a significant decrease in carbohydrate (~ 70 g) and fat consumption (~ 20 g); however, total protein intake did not change (Table 4).

Both the risk and non-risk allele groups experienced a significant decrease in body weight, fat mass, % body fat, trunk fat mass, and lower extremity fat mass (Tables 5 and 6); however, only the risk allele group experienced a significant decline in upper extremity fat mass (Table 6). There were no differences between groups for any of the body composition measures (Figs. 1, 2, 3 and 4; Tables 5 and 6) except percent body fat (Fig. 5).

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There was a significant increase in sAA, a marker of sympathetic nervous system (SNS) activity, in the risk allele group [17]; however, there were no between-group differences for the change in sAA. Moreover, there were no significant changes in salivary cortisol (Table 7).

To the authors’ knowledge, this is the first randomized controlled trial on the FTO gene that has examined the effect of caloric restriction on a group of normal weight men and women with several years of regular exercise training. The data from the current investigation demonstrates that the restriction of dietary energy from carbohydrate and fat result in a similar loss of fat mass in the risk versus non-risk allele groups. Interestingly, the change in percent body fat was significantly greater in the risk allele (− 1.3%) versus non-risk allele (− 0.8%) group. Though not significantly different, the risk allele group lost 1.1 kg of fat mass compared to 0.9 kg in the non-risk allele group. Both groups lost most of their fat mass from the trunk followed by the lower and upper extremities. In essence, it is clear that short-term energy restriction is effective regardless of whether one carries the ns for the three FTO SNPs that we examined. Although not significant, the risk allele group trended towards greater alterations in body composition.

The current investigation is a follow-up to the cross-sectional study conducted on 108 highly trained individuals that included professional mixed martial arts fighters, competitive distance runners, collegiate swimmers, stand-up paddlers, and recreational bodybuilders. In that prior investigation, it was found that C allele carriers of the FTO SNP rs1421085 had significantly higher fat mass and percent body fat versus the TT group. Interestingly, cortisol levels were significantly higher in the TT group relative to the C allele carriers thus demonstrating that resting cortisol is unrelated to body fat mass [11]. In a large-scale cross-sectional study of 846 healthy Finnish males of Caucasian origin, subjects were genotyped for the FTO SNP rs8050136. The AA genotype of the FTO SNP rs8050136 is associated with a higher BMI and greater waist circumference compared to the genotype CC. It was discovered that there was no relationship between the FTO gene and aerobic or neuromuscular exercise performance. Thus, aerobic fitness may not modify the effect of FTO variation on body composition traits [18]. Another group investigated whether body composition and metabolism were modulated by the FTO SNP rs9939609 in a group of young women engaged in exercise training. A group of 201 young Polish women were examined before and after the completion of a 12-week training program. Subjects with AA and AT genotypes had higher BMI during the entire study period compared with the TT genotype. Although BMI, basal metabolic rate, percent body fat, fat mass, fat-free mass, total body water, high-density lipoprotein, and glucose changed significantly during the training program, there were no differences between groups (i.e., those with the risk alleles, AA and AT, responded similarly as those that were the TT genotype) [19]. This further demonstrates that given the same exercise intervention, the adaptive response is similar between risk and non-risk allele groups.

According to Harbron et al. the risk alleles of the FTO polymorphisms were associated with poorer eating behaviors (e.g., higher hunger, internal locus for hunger, and emotional disinhibition scores), as well as a higher intake of high fat foods and refined starches and more depressive symptoms [4]. It has been suggested that specific macronutrient diet composition can influence the adaptive response as it relates to the FTO gene. Thus, it would seem plausible that dietary habits can modify the FTO gene risk allele influence on obesity [20]. For instance, in adolescents whose fat intake was below 30%, the A allele of rs9939609 was not associated with adiposity. Conversely, adolescents whose fat intake was between 30 and 35% of energy, the rs9939609 SNP was associated with a 1.9% higher body fat per risk allele and in those whose fat intake was higher than 35%, it was associated with a 2.8% higher body fat per risk allele. At least with this specific FTO SNP rs9939609, adiposity may be exacerbated in adolescents consuming high fat diets [21]. The current investigation showed that a decrease in energy consumption (~ 5–6 kcal/kg/day decrease) resulted in a fat mass loss with no change in fat-free mass. Our subjects consumed a relatively high protein diet (~ 2 g/kg/d) during the 4-week treatment. It is likely that the maintenance of fat-free mass during caloric restriction was due both to the high protein intake as well as the ~ 9 h per week of exercise training this cohort of subjects performed. Di Renzo et al. studied a group of 188 Italian subjects to determine the effects of a Mediterranean diet on body composition during a 4-week treatment. The FTO SNP rs9939609 was determined in this cohort. They discovered that although the diet reduced fat mass, the FTO genotype had no influence on the loss of fat mass [22]. Hubacek et al. analyzed the FTO SNP rs17817449 in 6024 adults aged 45–69 years to assess the role of diet and physical activity. This FTO variant was significantly associated with body mass index and basal metabolic rate; on the other hand, it was not associated with physical activity, total energy intake or with energy intakes from fat, carbohydrates, proteins or alcohol [23]. Zhang et al. conducted the most extensive study to date on the influence of a dietary intervention in obese adults and the FTO SNP rs1558902 [9]. The FTO SNP rs1558902 was genotyped in 742 obese adults who were randomly assigned to one of four diets differing in the proportions of fat, protein, and carbohydrate: the target percentages of energy derived from fat, protein, and carbohydrate in the four diets were 20, 15, and 65%; 20, 25, and 55%; 40, 15, and 45%; and 40, 25, and 35%. Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and computed tomography. They discovered that carriers of the rs15589002 risk allele (A) had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet, whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet. This data suggest that a higher protein diet may be beneficial for body composition those with the risk allele of the FTO variant rs1558902 [9]. Certainly at this point, it is unclear how diet and the FTO gene interact. However, based on the limited number of randomized controlled trials, it is evident that caloric restriction can produce a loss of fat mass regardless of one’s FTO genotype.

An association between an FTO SNP and cortisol levels was previously reported in a cross-sectional study of exercise-trained individuals where the non-risk allele group had higher cortisol levels [11]. Additionally, there is an association between high cortisol levels and obesity [24]. However, the current investigation found no change in cortisol (post minus pre) in either group. Also, despite the fact that sAA increased in the risk allele group, the differences between the groups (change in sAA) were no significantly different. Thus, it is not clear what relationship cortisol or sAA has with the FTO gene and changes in body composition in exercise-trained individuals.

Exercise-trained men and women that carry the risk alleles for the FTO SNPs (rs1421085, rs17817449 and rs9939609) had similar changes in body composition compared to those at normal risk after a 4-week period of energy restriction. The decrease in percent body fat was due exclusively to a loss of fat mass. Total body water did not change in either group; thus, we can rule out a decrease in percent body fat due to an elevation of total body water. At least in the short-term, individuals can lose fat mass in spite of their FTO genotype. Thus one can conclude that changes in body composition are unaffected by the FTO gene (i.e., energy restriction will produce a loss of fat mass whether one has the risk or non-risk alleles).