A fat mass and obesity-associated gene polymorphism influences fat mass in exercise-trained individuals

There is a powerful genetic influence on fat mass with heritability estimates ranging from 40 to 80% [1]. In particular, polymorphisms in the fat mass and obesity associated (FTO) gene are related to individual differences in food intake and energy balance [2] and can also influence skeletal muscle phenotype [3]. Multiple single nucleotide polymorphisms (SNPs) occur on the FTO gene that may influence adipogenesis and obesity [4‐6]. Since the obesity-associated SNPs are on the intron 1 region of the FTO gene, the mechanisms through which they influence body mass are uncertain. However, it has recently been shown in humans that a T-C SNP at position 53,767,042 on the FTO gene (rs1421085) causes an increase in IRX3 and IRX5 protein expression during early adipocyte differentiation in favor of energy-storing/white adipocytes over energy-dissipating/beige adipocytes. The critical downstream effect of this is increased energy conservation in the form of augmented fat storage [7].

Previous work has shown that exercise intervention can ameliorate the influence of FTO risky alleles on BMI on the FTO rs8050136 SNP [8, 9] and the rs9939609 SNP [10‐12]. However, due to the direct influence of the FTO SNP rs1421085 on early adipocyte differentiation, the effect of exercise training on body fat in the risky allele carriers of the rs1421085 SNP are less certain. The purpose of the study was to examine the relationship between FTO genotype and body composition in trained individuals. We also determined if salivary cortisol is related to fat mass in exercise-trained individuals.

The physical characteristics of the subjects were as follows (mean±SD): body weight 74.5±15.6 kg; bone mineral content 2.8±0.7 kg; fat mass 15.7±5.5 kg; lean body mass 55.9±14.4 kg; body fat percentage 21.6±7.0%. The population that we studied consisted of the following: 41 resistance-trained individuals (primarily recreational bodybuilders), 22 competitive stand-up paddlers/rowers, 15 professional fighters (i.e., MMA, boxing), 11 collegiate division II swimmers, 9 collegiate division II track and field athletes, 8 collegiate division II distance runners, 1 division II collegiate soccer player and 1 distance cyclist. Thus, 42 and 66 subjects primarily performed aerobic and anaerobic exercise, respectively. The percentage of the TT and C/− carriers that were aerobic athletes was 40% and 42%, respectively. Thus, no differences existed regarding the distribution of athlete type (aerobic versus anaerobic).

The current investigation found that C allele carriers had significantly higher fat mass and a body fat percentage relative to the TT group. Thus, even in a group of highly trained individuals, the risk allele was associated with higher body fat. One could speculate that in spite of intense exercise training, C allele carriers may still have greater fat mass than TT individuals. One might suggest that those who perform primarily endurance activities tend to carry less fat (i.e., fat mass and percent body fat). However, that was not the case in our investigation. We had an equal percentage of athletes that performed aerobic or anaerobic activities in the C/− and TT groups.

There is a dearth of studies on the FTO gene as it relates to an athletic or exercise-trained population. Eynon et al. found that the FTO A/T polymorphism was not associated with elite athletic status in a large cohort of European athletes (i.e., 266 endurance and 285 sprint/power athletes) [15]. Certainly this makes sense inasmuch as athletic performance, particularly in skill sports, cannot be predicted solely on the basis of body composition. Huuskonen et al. studied 846 healthy Finnish males and found that aerobic fitness does not modify the effect of FTO rs1421085 variation on body composition traits [16]. This is in agreement with our data showing that the percentage of endurance-trained individuals was equally represented in the TT and C/− genotypes. Heffernan et al. genotyped a group of non-athletes and elite rugby players for the FTO gene [17]. They discovered that T allele carriers had greater total body and total appendicular lean mass versus the AA genotype. Furthermore, the T allele was more common (94%) in selected elite rugby union athletes. Thus, at least in comparing athletes to non-athletes, the TT genotype is ostensibly more common.

A further aim of the study was to show whether cortisol is a pathway through which C allele carriers have greater levels of body fat. This possibility has arisen, at least in part, because previous work has shown that exercise increases cortisol levels [18] and there exists an association between high cortisol levels and obesity [19]. Interestingly, we found that the TT FTO rs1421085 group had significantly higher cortisol levels than the risky C/− group. Given that the TT group had significantly lower body fat percentage and fat mass than the C/−group, this finding supports that notion that cortisol is not related to increased fat mass in exercise-trained individuals. Although it is unclear why the TT genotype relates to higher cortisol levels, one might speculate that the TT group has a greater ratio of brown to white adipose tissue than the C/− group. This could result in higher cortisol levels due to the increased energy need in the form of increased calorie expenditure [7]. In support of this idea, a previous study found that higher cortisol levels were associated with increased activity in brown adipose tissue [20]. However, while this idea is intriguing, more work will need to be done to clarify the relationship between FTO rs1421085 genotype, brown vs. white adipose tissue, and cortisol.

A major limitation of our investigation is the cross-sectional design. For instance, it would be intriguing to see if exercise-trained individuals that are TT can lose more fat mass than their C/− counterparts when given the same hypocaloric diet. Based on the cross-sectional data from our investigation, one would predict that TT individuals should lose more fat mass, similar to a previous study that investigated a different FTO SNP [21] since the common FTO polymorphisms all associate with obesity and there is high linkage disequilibrium between them [22, 23]. In particular, Zhang et al. tested the effect of FTO variant on weight loss in response to 2-year diet interventions in 742 obese adults [21]. They discovered that carriers of the risk allele of the FTO variant rs1558902 had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet. Thus, at least in this cohort of obese individuals, a high protein diet may indeed be optimal choice as it relates to changes in body composition. Whether such a strategy would work for an exercise-trained population that has a low body fat percentage is unknown. Future work is needed to elucidate the role of protein intake on modifying body composition in exercise-trained individuals.

In summary, the cross-sectional data from this investigation suggest that in spite of intense athletic training, C allele carriers (FTO gene, rs1421085) tend to have a greater percentage of fat mass; however, it should be noted that the C/− group in our investigation still have quite low body fat percentages. Thus, it is clear that exercise training can dramatically modify one’s phenotype despite a purported genetic limitation.