The Effect of FTO rs9939609 Gene Polymorphism on Exercise-Induced Fat Oxidation

The Effect of FTO rs9939609 Gene Polymorphism on Exercise-Induced Fat Oxidation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Effect of FTO rs9939609 Gene Polymorphism on Exercise-Induced Fat Oxidation Necdet Apaydin, Ahsen Eren, Cagri Dogan, Gokhan Ipekoglu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8279716/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 6 You are reading this latest preprint version Abstract Background The FTO rs9939609 polymorphism is well-studied for obesity and metabolism, but its effect on exercise-induced substrate oxidation remains unclear. This study aimed to examine the impact of the FTO rs9939609 polymorphism on fat oxidation (FAT), carbohydrate oxidation (CHO), and respiratory exchange ratio (RER) during and after exercise in sedentary young adult males. Methods A total of 45 male participants were recruited and genotyped for FTO rs9939609. Participants underwent an incremental treadmill exercise test, during which RER, FAT, and CHO oxidation rates were measured using indirect calorimetry. Substrate oxidation was assessed during both exercise and a 15-minute post-exercise recovery period. Data was analyzed according to recessive and dominant genetic models. Results The AA genotype group exhibited a significantly lower RER during compared to the AT + TT group, indicating a greater reliance on fat oxidation. Similarly, AA carriers had higher fat oxidation than AT + TT, while carbohydrate oxidation was significantly lower in AA compared to AT + TT. This trend persisted in the post-exercise recovery phase, with AA individuals maintaining higher fat oxidation and lower RER, though differences were less pronounced. Conclusion The findings suggest that the FTO rs9939609 polymorphism influences substrate oxidation in a recessive manner. AA genotype carriers oxidize fat over carbohydrates during moderate-intensity exercise and post-exercise recovery, while individuals with at least one T allele exhibit higher carbohydrate utilization. These results imply that genetic factors may play a role in metabolic responses to exercise. Future studies with larger, diverse populations and longitudinal training interventions are needed to confirm these findings. Health sciences/Biomarkers Health sciences/Medical research FTO rs9939609 genetic polymorphism fat oxidation carbohydrate oxidation Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction The continuity of anabolic and catabolic processes in the body requires energy. This energy is provided through the oxidation of nutrients in the cells. Carbohydrates (CHO) and fat are the most essential energy sources for the body, playing a critical role in meeting energy demands. While numerous factors influence energy needs, one of the most significant is physical activity. The energy required during exercise varies depending on the intensity, duration, type of exercise, and an individual's fitness level. The rate of substrate oxidation during physical activity is affected by various factors such as age, gender, body composition, exercise duration, exercise mode, diet, and training status[ 1 ] . Fat oxidation rate is regulated by multiple variables, including nutrition, muscle glycogen content, hormones, and an individual's fitness status. However, one of the most critical determinants is exercise intensity [ 2 ]. Maximal oxygen consumption capacity (VO 2 max) is one of the primary references for defining exercise intensity. Exercises at approximately 65% of VO 2 max or below are classified as light to moderate intensity, whereas those above 65% are considered high-intensity exercises. It is well known that fat oxidation rates reach their highest levels during light to moderate-intensity exercise, but as intensity increases beyond this level, the amount of oxidized fat decreases[ 3 ] .Additionally, repeated exercise performed in two sessions has been found to result in higher fat oxidation compared to a single continuous session [ 4 ]. Fat oxidation rate and quantity vary depending on several factors such as nutrition, hormones, body glycogen content, and exercise [ 5 ]. In recent years, the role of genetic factors in obesity, fat accumulation, and fat oxidation has garnered increasing interest. Genome-wide association studies (GWAS) have reliably demonstrated that SNPs located in the first intron of the FTO gene are strongly associated with increased BMI and fat accumulation across different ages and populations [ 6 ]. Several single nucleotide polymorphisms (SNPs) within the FTO gene have been linked to increased body mass index (BMI), waist circumference, total body mass, and fat mass levels[ 7 ]. A recent study found that the FTO rs9939609 polymorphism is associated with maximal fat oxidation (in both absolute and relative values) regardless of gender and BMI [ 8 ]. The FTO gene, which was the first obesity-susceptibility gene discovered through GWAS in European individuals with type 2 diabetes, is located on chromosome 16, in the 16q12.2 region. This gene is highly expressed in the hypothalamus, pituitary, and adrenal glands, which are involved in body weight regulation and satiety. Various variants of the FTO gene have been shown to play a regulatory role in food intake control and energy balance [ 9 ]. The obesity-risk variant of the FTO rs9939609 polymorphism has been associated with increased appetite and higher energy intake in adults[ 10 ]. Adults carrying the A allele of the FTO rs9939609 gene have been found to have higher body weight and BMI compared to those carrying the T allele. Individuals who are homozygous for the obesity-risk A allele have been reported to have a 1.7-fold higher risk of obesity compared to those who are homozygous for the lower-risk T allele [ 6 ]. Furthermore, individuals with the TT genotype have been found to have significantly higher hunger and general appetite levels than those with the AT genotype [ 8 ]. Additionally, AT carriers have demonstrated lower fat oxidation values compared to TT genotypes. The presence of the TT allele in the FTO rs9939609 gene appears to serve as a protective factor against obesity and cardiometabolic diseases by contributing to better metabolic capacity and flexibility [ 8 ] Studies on the effect of the FTO rs9939609 gene polymorphism on exercise-induced fat oxidation are rather limited. Although numerous factors influence fat oxidation, the role of genetic composition in this process has not been fully elucidated. Therefore, determining the impact of the FTO rs9939609 polymorphism on fat oxidation during and after exercise may contribute to the development of individualized exercise and dietary strategies. The findings of this research could guide the development of new approaches for the prevention and treatment of obesity and metabolic diseases. Materials and Methods Study Population and Sample The study included 45 young adult male volunteers aged between 20 and 30 years, who had no health-related restrictions preventing them from exercising and had not engaged in regular physical activity in the past three years (sedentary). Prior to the study, approval was obtained from the Non-Interventional Clinical Research Ethics Committee of Ordu University Health Sciences Institute (Approval No: 2024/85). The exercise protocol of the study was conducted in the Performance Laboratory of Ordu University Faculty of Sports Sciences. All participants were informed about the study, including potential benefits and risks. Written informed consent was obtained in accordance with the Helsinki Declaration [ 11 ] Determination of Body Weight The participants’ physical characteristics were determined by measuring their height and weight. Height measurements were taken using a stadiometer (Holtain Ltd., Crymych, UK) while participants stood barefoot with their heads upright. Body weight was measured using an electronic scale (Seca 700; Seca GmbH, Hamburg, Germany). Indirect Calorimetry A portable gas analyzer (Cosmed K5, Cosmed, Rome, Italy) was used in the study. Prior to each test, room air calibration, reference gas calibration (with a gas mixture of 16% O 2 and 5% CO 2 ), delay calibration, and turbine calibration were performed. Once the participant was ready, the analyzer was securely attached to allow free movement. Respiratory parameters were recorded using specialized software, and fat and carbohydrate oxidation rates were calculated using the following stoichiometric equations from Frayn (1983)[ 12 ]: Carbohydrate oxidation = 4.55 × VCO 2 – 3.21 × VO 2 Fat oxidation = 1.67 × VO 2 – 1.67 × VCO 2 The percentage of fat and carbohydrate oxidation during exercise tests was calculated using the formula proposed by Dumortier et al. (2005): % Fat = [(1-RER)/0.29] × 100 • % CHO = [(RER-0.71)/0.29] × 100 Determination of Maximal Aerobic Power (MaxVO 2 ) and Maximal Fat Oxidation Rate After an adequate warm-up, participants performed an incremental treadmill test on a Woodway treadmill. Fat oxidation rates were measured both during exercise and for 15 minutes post-exercise (Recovery) to evaluate metabolic flexibility and recovery response using a portable gas analyzer (K5, Cosmed, Rome, Italy). Modified Bruce Protocol The Bruce protocol began with the collection of baseline values using the gas analyzer. After a standard warm-up, the test started at 1.7 mph with a 10% incline. Every three minutes, the speed and incline were increased until the participant reached exhaustion. The test consisted of seven stages, with corresponding incline, speed, and duration values presented in Table 1 . Table 1 Modified Bruce Protocol Level Speed (km/h) Incline (%) Duration (min) Total Duration (min) 0 2.7 0 3 3 1 2.7 5 3 6 2 4.0 12 3 9 3 5.4 14 3 12 4 6.7 15 3 15 5 8.0 15 3 18 6 8.8 15 3 21 7 9.6 15 3 24 Genetic Analysis Genomic DNA extraction was performed using the DiaRex® Whole Blood Genomic DNA Extraction Kit (Cat. No: BLD-5295, Diagen, Ankara). The process involved lysis, proteinase K digestion, ethanol precipitation, and column-based purification to obtain high-quality genomic DNA. The nucleic acid concentrations of the extracted genomic DNA samples were measured using a Colibri Microvolume Spectrometer (Titertek-Berthold, Germany). Real-time PCR was used to analyze specific FTO rs9939609 gene regions. The primers were synthesized (Biomers, Germany) and reactions were performed using TaqProbe 2X qPCR MasterMix (Sansifast, UK). PCR amplification was carried out using a BioRad CFX-96 system. Data Analysis Statistical analyses were performed using IBM SPSS Statistics 26.0. The Shapiro-Wilk test was used to assess normality. Descriptive statistics were reported as mean ± standard deviation. Independent Sample t-tests (for two groups) and one-way ANOVA (for three groups) were conducted. Chi-square tests (χ²) were used to evaluate Hardy-Weinberg equilibrium. Statistical significance was set at p 0.05, the observed genotype frequencies did not significantly deviate from HWE expectations, indicating that the sample population follows normal Mendelian inheritance patterns and that no selection bias or population stratification was present. The baseline characteristics of participants, categorized by FTO rs9939609 genotype, are presented in Fig. 1 . No significant differences were observed among genotype groups for age (p = 0.406), height (p = 0.929), weight (p = 0.624), or BMI (p = 0.620). The mean age of participants was 23.26 ± 2.32 years, and their average BMI was 24.43 ± 4.17 kg/m². Although slight variations were noted, with the TA genotype group showing the highest mean BMI (25.06 ± 4.97) and the AA group having the lowest (23.42 ± 1.89), these differences did not reach statistical significance (p > 0.05). During exercise, TT vs. AA + AT groups had nearly identical metabolic values. For instance, mean RER was 0.845 in TT vs. 0.839 in the AA + AT group, and fat oxidation averaged 53.1 vs. 56.5 units, respectively – differences that were not statistically significant (p = 0.505 for RER; p = 0.339 for fat)​. Carbohydrate use was also similar (46.9 vs 43.5 units, p = 0.331)​. In the recovery phase, the two groups remained very close: RER 0.997 (TT) vs. 0.994 (AA + AT, p = 0.911), fat oxidation 34.8 vs. 35.9 (p = 0.804), and CHO oxidation 65.45 vs. 64.05 (p = 0.755) no meaningful differences (Table 2 .). Table 2 Evaluation of RER, Fat Oxidation, and Carbohydrate Oxidation Based on the Dominant Model (TT vs. TA + TT) Variable Dominant Model n Mean sd t p During Exercise RER TT 17 ,845 ,044 ,672 ,505 TA + TT 28 ,839 ,045 FAT TT 17 53,10 11,595 -,966 ,339 TA + TT 28 56,54 11,669 CHO TT 17 46,94 11,509 ,984 ,331 TA + TT 28 43,45 11,669 In Recovery RER TT 17 ,9971 ,08793 ,113 ,911 TA + TT 28 ,9942 ,08335 FAT TT 17 34,8196 15,1580 -,250 ,804 TA + TT 28 35,9230 13,8974 CHO TT 17 65,4510 15,4076 ,315 ,755 TA + TT 28 64,0504 13,8983 *p < 0,05 The mean RER value for individuals with the AA genotype was 0.812 ± 0.035, whereas for those with the AT + TT genotype, it was 0.849 ± 0.044. During exercise, the t-test revealed a statistically significant difference between the two groups (t =-2.536; p = 0.026), with the AT + TT genotype group having a significantly higher RER value than the AA genotype group. At recovery, AA also showed a lower mean RER (0.947 vs. 1.006 for AT + TT), though this gap did not reach significance (p = 0.075)​ (Table 3 .). Table 3 Evaluation of RER, Fat Oxidation, and Carbohydrate Oxidation Based on the Recessive Model (AA vs. AT + TT) Variable Recessive Model n Mean sd t p During Exercise RER AA 8 ,812 ,035 -2,536 , 026* AT + TT 37 ,849 ,044 FAT AA 8 64,507 7,713 ,389 , 004* AT + TT 37 53,325 11,446 CHO AA 8 35,494 7,716 -3,398 , 004* AT + TT 37 46,695 11,409 In Recovery RER AA 8 ,9474 ,09247 -1,820 ,075 AT + TT 37 1,0057 ,07979 FAT AA 8 44,4624 16,7125 2,033 , 048* AT + TT 37 33,5697 13,0897 CHO AA 8 55,5376 16,7125 -2,038 , 048* AT + TT 37 66,5345 13,2118 *p < 0,05 Individuals with the AA genotype consistently exhibited higher fat oxidation rates than AT + TT. In the exercise phase, the AA group oxidized on average 64.507 ± 7.713 units of fat vs. 53.325 ± 11.446 in the AT + TT group – a significant increase in the AA genotype (p = 0.004)​ Notably, this difference persisted in the recovery phase: AA genotype fat oxidation averaged 44.46 vs. 33.57 for AT + TT, indicating 33% greater fat use by AA (this difference was also significant, p = 0.048) (Table 3 .). The AA genotype showed lower carbohydrate oxidation compared to AT + TT, complementing their higher fat use. During exercise, AA individuals oxidized 35.494 ± 7.716 units of CHO on average, whereas the AT + TT group oxidized 46.695 ± 11.409 – a significant difference (p = 0.004). At recovery, AA continued to use less carbohydrate (55.54 vs. 66.53 in AT + TT, p = 0.048)​ (Table 3 .). Figure 2 illustrates the respiratory exchange ratio (RER) values during the exercise and recovery protocols. The analysis indicated that the AA genotype group exhibited significantly lower RER values compared to the AT + TT group during the exercise session (p < 0.05). Figure 3 presents the fat oxidation rates for both groups. The data showed that individuals with the AA genotype achieved significantly higher fat oxidation rates than the T-allele carriers (AT + TT) during both the exercise and recovery periods (p < 0.05). Conversely, carbohydrate oxidation rates, as shown in Fig. 4 , were significantly lower in the AA genotype group compared to the AT + TT group during the exercise protocol (p < 0.05). A similar trend of lower carbohydrate oxidation in the AA group persisted during the recovery phase (p < 0.05). Discussion The results of this study add to a mixed body of literature on FTO polymorphisms and substrate oxidation during exercise. Some prior studies have reported little to no effect of the FTO rs9939609 variant on fuel utilization. For example, García-Pastor et al. found no significant differences in maximal fat oxidation (MFO) during exercise across TT, AT, and AA genotypes (MFO 0.35–0.37 g/min in all groups, p = 0.702)​. Their work concluded a “lack of genetic association” between FTO genotype and fat-burning capacity in healthy young adults​. This aligns with other research suggesting that FTO’s influence on energy expenditure may be modest. Danaher et al. also observed similar metabolic flexibility between FTO genotypes in response to diet, implying minimal differences in substrate use under acute challenges​ [ 13 ] However, our findings diverge from studies that do report genotype-dependent differences. Notably, Ponce-González et al. observed that individuals carrying the risk A allele had altered exercise fuel metabolism​ In their study, heterozygotes (AT) showed lower fat oxidation rates during exercise compared to TT homozygotes. Interestingly, those authors noted that homozygous AA individuals did not have further reductions in fat use – in fact, AA participants’ fat oxidation was comparable to TT subjects​. This unexpected pattern (TT > AT, with AA ≈ TT in fat utilization) suggests a non-linear or threshold effect of the FTO variant, rather than a simple dose-response. Our results lend support to a recessive model of effect: we found that only AA homozygotes differed significantly from others, with higher fat oxidation and lower RER than AT/TT. This contrasts with the hypothesis that obesity-risk A allele necessarily impairs fat burning​. Instead, our AA group oxidized more fat (and less carbohydrate) during exercise, an outcome that is opposite to what one might predict for an “obesity-prone” genotype. Such discrepancies underscore that the relationship between FTO genotype and substrate oxidation is complex and may depend on study design, population, or statistical models. Indeed, the FTO gene has been widely linked to BMI and adiposity​, but its impact on exercise metabolism appears subtler and context-dependent. Consistent with our findings, one recent report noted that associations of FTO with metabolic traits were most evident when comparing AA vs. T-allele carriers (recessive model), even though no overall genotype effect on MFO was seen​ [ 8 , 13 ]. Thus, while our study’s observation (enhanced fat oxidation in AA genotype) is somewhat atypical, it highlights the need to consider different genetic models and suggests that previous null findings could mask effects present only in homozygous risk carriers. Several biological mechanisms might explain how the FTO rs9939609 variant influences fuel selection during exercise. One possibility involves differences in insulin sensitivity and metabolic flexibility. The A allele of rs9939609 has been associated with elevated fasting insulin and glucose levels, indicating a trend toward insulin resistance in carriers [ 14 ]​. Insulin resistance could limit muscular uptake and oxidation of glucose, forcing greater reliance on fatty acids for energy during exercise. In line with this, our AA participants (who likely have the greatest genetic predisposition to insulin resistance) showed the lowest carbohydrate use and RER. Impaired insulin signaling in muscle can blunt carbohydrate oxidation, effectively “pushing” metabolism toward fat, especially at moderate intensities. Interestingly, in vivo muscle studies support this interpretation: Grunnet et al. reported that homozygous A carriers exhibit higher hepatic insulin resistance along with faster phosphocreatine recovery in oxidative muscle fibers after exercise​. A faster PCr recovery half-time suggests enhanced mitochondrial oxidative capacity or efficiency in regenerating ATP. This paradoxical finding – risk-allele carriers with seemingly better muscle oxidative recovery – could reflect an adaptive metabolic response or muscle fiber-type differences. Indeed, skeletal muscle characteristics may play a role. A genetic study by Guilherme et al. noted that the A allele is associated with a lower proportion of slow-twitch (type I) oxidative fibers in muscle. Typically, having fewer type I fibers would reduce fat oxidation capacity (since type I fibers are highly fat-adaptive), potentially making carriers more reliant on glycolytic (carbohydrate-fueled) pathways. Yet, in our untrained sample, the AA group still oxidized more fat; this might indicate that other compensatory mechanisms (such as those related to insulin or mitochondria) outweighed fiber-type influences, or simply that our AA subjects, despite genetic risk, had not developed the phenotypic traits (e.g. lower oxidative capacity) often seen in overweight individuals. It is also plausible that FTO genotype affects hormonal responses that modulate substrate use. FTO is highly expressed in the brain’s energy-regulation centers, and A alleles have been linked to higher circulating ghrelin (hunger hormone) and appetite. While appetite per se does not acutely alter exercise metabolism, chronically higher caloric intake could lead to differences in body composition or muscle metabolism over time. We controlled for BMI (our groups were weight-matched), but subtle differences in muscle lipid content or enzyme levels could exist. Additionally, FTO-related genetic variation might alter expression of genes involved in mitochondrial function. Research has shown that overexpression of FTO in muscle cells can induce lipid accumulation and mitochondrial dysfunction​ (Bravard et al. 2011). If risk-allele carriers have higher FTO activity in muscle, they might experience changes in how substrates are oxidized – for instance, accumulating intramuscular fat that could paradoxically serve as fuel during exercise. Another mechanism to consider is the role of FTO in adipose tissue. The intronic FTO variant has been found to influence adipocyte browning through downstream targets IRX3/IRX5, affecting whole-body energy expenditure. The A allele tends to reduce basal lipolysis – in vitro studies showed 22% lower spontaneous fat cell lipolysis in A carriers compared to TT​ and promotes fat storage in adipocytes​ (Wahlen et al. 2008). At face value, reduced baseline lipolysis would suggest less fatty acid availability for oxidation. However, during exercise, catecholamine-stimulated lipolysis was reported to be similar between genotypes​, meaning that under exercise stress, A carriers can mobilize fat as effectively as T carriers. Our data might indicate that once mobilized, those fatty acids were readily oxidized by AA individuals. It is conceivable that the metabolic inflexibility often attributed to the FTO risk genotype (such as difficulty switching between fuels) manifests in a nuanced way: in the fasted, moderate-intensity exercise state, AA individuals might remain in a fat-burning mode to a greater extent, whereas T-allele carriers shift to carbohydrates more readily. In summary, the FTO rs9939609 variant likely exerts its effects on exercise metabolism via a combination of factors – insulin dynamics, muscle fiber composition, mitochondrial function, and adipose tissue biology – rather than a single pathway. Further mechanistic studies (e.g. muscle biopsies and fuel utilization tests across varying conditions) are warranted to pinpoint how this gene alters the interplay between carbohydrate and fat metabolism. Our findings, if confirmed, could have noteworthy implications for personalized exercise recommendations and metabolic health strategies. One immediate consideration is in the context of obesity prevention and weight management. Carriers of the FTO A allele are known to have a higher propensity for weight gain, largely due to increased appetite and caloric intake. Regular exercise is often recommended to mitigate this risk, and our results reinforce that advice. In fact, prior research shows that an active lifestyle can attenuate the BMI-increasing effect of FTO risk variants by roughly 27–30% [ 15 ]. For individuals with the high-risk AA genotype, exercise might be doubly important – not only to burn calories, but also to improve or maintain metabolic flexibility. The observation that AA carriers in our study oxidize fat well at moderate intensity suggests they could leverage steady-state aerobic exercise as an effective way to utilize excess fat stores. Exercise programs emphasizing endurance activities (e.g. cycling, running at moderate intensity) might align with their intrinsic tendency to burn fat, potentially aiding in preventing fat accumulation. On the other hand, the lower reliance on carbohydrates in AA individuals might indicate a need to improve their capacity for high-intensity, glycolytic work. Thus, a balanced program that includes some high-intensity training could help risk-allele carriers enhance carbohydrate metabolism and insulin sensitivity, counteracting any predisposition toward insulin resistance. Future research should include diverse populations to see if our findings hold across genders, age ranges, and fitness levels. Third, the study design was cross-sectional, measuring acute exercise substrate oxidation at a set intensity. We did not assess a full range of intensities or the time-course of adaptation. It would be informative to examine metabolic responses over a spectrum of exercise intensities (from low to high) to determine if genotype effects are more pronounced at particular workloads or during recovery. Measuring the entire fat oxidation curve and the point of maximal fat oxidation (Fatmax) for each genotype group could reveal nuances that a single-intensity measurement might miss. Additionally, we relied on indirect calorimetry equations to estimate fat and CHO oxidation, which, while standard, are subject to assumptions (e.g. negligible protein oxidation, steady-state conditions). Any systematic error in these estimates would affect all participants similarly, but it is something to consider in interpreting absolute values. We also did not directly measure potential mediators such as insulin levels, free fatty acid concentrations, or muscle glycogen content. Including such physiological measurements could help explain why genotypes differ in RER. The present study has certain limitations that should be noted. Primarily, the sample size for the homozygous allele (AA) group was relatively small (n = 8). However, the observation of statistically significant differences in substrate oxidation, despite this limited sample size, suggests that the physiological effect of the genotype is robust and pronounced. Therefore, while replication in larger cohorts is necessary for broader generalizability, the findings presented here provide valuable and strong evidence regarding the metabolic impact of the FTO variant. Secondly, this study focused exclusively on the FTO rs9939609 polymorphism; given the polygenic nature of metabolic regulation, future studies should address the combined effects of multiple genetic variants on exercise metabolism. Overall, having one A allele (heterozygous AT) did not significantly alter fuel utilization compared to TT. All comparisons between the TT genotype and the combined non-TT group showed p > 0.05, indicating no statistically significant metabolic difference. In conclusion, while our study provides novel insights into FTO rs9939609 and exercise fuel use, it raises as many questions as it answers. By addressing the limitations above, future work can clarify the role of FTO in exercise metabolism and determine how to best apply this knowledge for improving health and performance. The significance of our findings lies in contributing to a more nuanced understanding of “obesity genes”: rather than simply predisposing one to weight gain, FTO genotype may subtly shape how the body derives energy during physical activity an insight that could eventually be leveraged in personalized nutrition and exercise guidelines for more effective obesity prevention and fitness optimization.​ Declarations Author Contribution Statement: All authors contributed to the conceptualization, design, and literature review of the study. The identification of participants, providing information about the study, obtaining informed consent, inclusion in the study, and collection of the necessary documents were carried out by A.E., N.A. and G.I. The design of primers/probes required for the study, genetic analyses, and appropriate sample collection from participants under suitable conditions were performed by C.D. All authors contributed to the writing of the manuscript and its translation into English. Ethics approval: Prior to the study, approval was obtained from the Non-Interventional Clinical Research Ethics Committee of Ordu University Health Sciences Institute (Approval No: 2024/85). The exercise protocol of the study was conducted in the Performance Laboratory of Ordu University Faculty of Sports Sciences. All participants were informed about the study, including potential benefits and risks. Written informed consent was obtained in accordance with the Helsinki Declaration. Competing Interests: The authors have no relevant financial or non-financial interests to disclose Funding: This research was supported by the Ordu University Scientific Research Project Office as a master's thesis under project number B-2414. Acknowledgments: The authors extend their heartfelt appreciation to all volunteers who took part in this study. The participants' engagement, commitment, and valuable contributions played a significant role in the successful execution of the research. References Ipekoğlu G, Balcı ŞS. Comparison between continuous and intermittent submaximal exercise at the intensity of maximal fat oxidation. J Hum Sci. 2016; 13:4604–4612. Romijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, Wolfe RR. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol. 1993; 265:E380–391. Achten J, Gleeson M, Jeukendrup AE. Determination of the exercise intensity that elicits maximal fat oxidation. Med Sci Sports Exerc. 2002; 34:92–97. Goto K, Ishii N, Mizuno A, Takamatsu K. Enhancement of fat metabolism by repeated bouts of moderate endurance exercise. J Appl Physiol. 2007; 102:2158–2164. Purdom T, Kravitz L, Dokladny K, Mermier C. Understanding the factors that effect maximal fat oxidation. J Int Soc Sports Nutr. 2018; 15:3. Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316:889–894. Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007; 3:e115. Ponce-Gonzalez JG, Martinez-Avila A, Velazquez-Diaz D, Perez-Bey A, Gomez-Gallego F, Marin-Galindo A, et al. Impact of the FTO gene variation on appetite and fat oxidation in young adults. Nutrients. 2023; 15:2196. Marginean CO, Marginean C, Melit LE. New insights regarding genetic aspects of childhood obesity: a minireview. Front Pediatr. 2018; 6:271. Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity. 2008; 16:1961–1965. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013; 310:2191–2194. Frayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983; 55:628–634. García-Pastor T, Muñoz-Puente I, Pérez-Pelayo M, Púa I, Roberts JD, Del Coso J. Maximal Fat Oxidation During Exercise in Healthy Individuals: Lack of Genetic Association with the FTO rs9939609 Polymorphism. Genes (Basel). 2024;16(1):4. Grunnet LG, Brons C, Jacobsen S, Nilsson E, Astrup A, Hansen T, et al. Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibers and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609. J Clin Endocrinol Metab. 2009; 94:596–602. Kilpelainen TO, Qi L, Brage S, Sharp SJ, Sonestedt E, Demerath E, et al. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 2011; 8:e1001116. Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Under Review Version 1 posted Review # 1 received at journal 19 Jan, 2026 Reviewer # 1 agreed at journal 19 Jan, 2026 Reviewers invited by journal 07 Dec, 2025 Editor assigned by journal 05 Dec, 2025 Submission checks completed at journal 05 Dec, 2025 First submitted to journal 04 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8279716","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":556611614,"identity":"e7cf57ac-fbee-4bbc-8b56-ed88b1b09205","order_by":0,"name":"Necdet Apaydin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/0lEQVRIiWNgGAWjYJACCShtcIChgoGxAUkEj5YEmJYzcC0GxGlhYGwjQos5e/PDGx9/2OXxz0jeeLhwno3shgPMB2/zMPzJx6XFsueYseWMhORiiRtpBYdnbksz3nCALdmah8HAsgGHFoMbOWzSPAnMiQ03cgwO8247nLjhAI+ZNFALTpcZ3H/DJv0noT5xPljLHJAW/m/4tdzgYZNmSACqBGtpANvChl/LmTRjy56048WGZ54VHOY5lmY88zCbseUcA2PcWo4ffnjjh011ntzx5M2feWpsZPuOA8PwTYUc/ogBggQGgQQokxlsFCENIC38BwirGgWjYBSMgpEJABPjWqJdKKHFAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8930-3205","institution":"Ordu University","correspondingAuthor":true,"prefix":"","firstName":"Necdet","middleName":"","lastName":"Apaydin","suffix":""},{"id":556611615,"identity":"691c6f53-4b77-416d-8d74-e61718d6440c","order_by":1,"name":"Ahsen Eren","email":"","orcid":"","institution":"Ordu University","correspondingAuthor":false,"prefix":"","firstName":"Ahsen","middleName":"","lastName":"Eren","suffix":""},{"id":556611616,"identity":"96229684-ab2b-4067-a5d0-321d00c3c341","order_by":2,"name":"Cagri Dogan","email":"","orcid":"","institution":"Ordu University","correspondingAuthor":false,"prefix":"","firstName":"Cagri","middleName":"","lastName":"Dogan","suffix":""},{"id":556611617,"identity":"ba159c50-bba8-4ceb-83da-2f9c3243a30f","order_by":3,"name":"Gokhan Ipekoglu","email":"","orcid":"","institution":"Ordu University","correspondingAuthor":false,"prefix":"","firstName":"Gokhan","middleName":"","lastName":"Ipekoglu","suffix":""}],"badges":[],"createdAt":"2025-12-04 13:15:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8279716/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8279716/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97900378,"identity":"b99bfddc-329e-486a-a32c-2631005f540c","added_by":"auto","created_at":"2025-12-10 15:45:26","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97385,"visible":true,"origin":"","legend":"","description":"","filename":"Figure1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/b9c481b70a82df0fc85e24d2.docx"},{"id":97882813,"identity":"60eece26-9147-466a-8868-43c396f346de","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":71206,"visible":true,"origin":"","legend":"","description":"","filename":"Manuscript.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/047264e87fb9a5b1ea3c4e1c.docx"},{"id":97882817,"identity":"0b7488f8-c208-48be-8981-439a4a1322f9","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":47270,"visible":true,"origin":"","legend":"","description":"","filename":"Figure2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/036255cf4f1895d67cf3d1b8.docx"},{"id":97882815,"identity":"afaef296-7585-4ed3-b313-c87f49eecc04","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15185,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/1872cd5ff58221ca036be37f.docx"},{"id":97899467,"identity":"b7e4d398-e30b-421e-9c0c-dd9605a34686","added_by":"auto","created_at":"2025-12-10 15:44:37","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":59215,"visible":true,"origin":"","legend":"","description":"","filename":"Figure3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/dd5be618e38e1350617cdd0e.docx"},{"id":97900768,"identity":"34a5e150-40ea-4ada-8f3a-6f710705e9be","added_by":"auto","created_at":"2025-12-10 15:45:51","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16918,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/01643d3935243dc0414f96a6.docx"},{"id":97882825,"identity":"2bfe9c89-09b3-4c83-a069-f95ad6608720","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":54910,"visible":true,"origin":"","legend":"","description":"","filename":"Figure4.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/bab124aeecbddd4429af06e1.docx"},{"id":97882822,"identity":"0e64ddb1-4933-4811-b341-4c8cf928445c","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17206,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/423454e42425df750472adeb.docx"},{"id":97899064,"identity":"d2c3b77f-430f-4c37-ba81-4fd592c0d5da","added_by":"auto","created_at":"2025-12-10 15:41:00","extension":"json","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6022,"visible":true,"origin":"","legend":"","description":"","filename":"2025EJCN1402.json","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/5d6ed69f793ccfd1502be4e6.json"},{"id":97882837,"identity":"0bdaa7e0-a10f-42af-9e3f-993478f342bf","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":82109,"visible":true,"origin":"","legend":"","description":"","filename":"2025EJCN14020enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/23f58ead47acef8fb4d71c2f.xml"},{"id":97882828,"identity":"a9f02db3-0fe4-4d5c-a5a6-7758e959947c","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"jpeg","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":82744,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/be24078f6bc8af225b8f16ac.jpeg"},{"id":97900957,"identity":"d3b2afe0-dd8d-472d-bf39-3af3589c4503","added_by":"auto","created_at":"2025-12-10 15:46:12","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":32566,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/d0e1a7f4f5bfa4bd88d89074.jpeg"},{"id":97882833,"identity":"54f3da43-2579-4a35-af4c-f4faab5396be","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"jpeg","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":44483,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/6b2eb6585f025149d24bc2d2.jpeg"},{"id":97882834,"identity":"03c7ccc5-2dc1-46fe-86f4-d737a8fa0fea","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"jpeg","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":40175,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/c79465d8fcb8432234acc8d6.jpeg"},{"id":97882832,"identity":"a9025671-f1c7-4393-9d4f-0e58e48752ee","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":35677,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/85cb353185f019a438a40956.png"},{"id":97899900,"identity":"7ba550da-e1ad-43d2-8ead-697f7570e8be","added_by":"auto","created_at":"2025-12-10 15:45:02","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10199,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/2691b79058eb4a596bdee279.png"},{"id":97900376,"identity":"a0e6cce4-2e95-494b-8ba3-b782487b3746","added_by":"auto","created_at":"2025-12-10 15:45:26","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12644,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/5ddf8a680950fe6cc1a8a3d2.png"},{"id":97900853,"identity":"4e44ce68-044f-407a-a690-9f0af9281854","added_by":"auto","created_at":"2025-12-10 15:46:00","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":12495,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/36c9c71573c5d44f5dad2e3d.png"},{"id":97900758,"identity":"31085af3-2b92-4383-8de1-a19972dcb8e5","added_by":"auto","created_at":"2025-12-10 15:45:50","extension":"xml","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":80189,"visible":true,"origin":"","legend":"","description":"","filename":"2025EJCN14020structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/f735a6e82750def0feaa1ceb.xml"},{"id":97882836,"identity":"9156f3c0-71ab-470b-a091-a24438a4cde3","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"html","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":87915,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/101abecd3ee030628a096576.html"},{"id":97900340,"identity":"2f7980b0-3167-4169-8131-4e91e7f774ef","added_by":"auto","created_at":"2025-12-10 15:45:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":263343,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline characteristics of participants by FTO rs9939609 genotype\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/7b4586888ab498b0657d46ce.png"},{"id":97900108,"identity":"c45f8b8c-45e9-4add-9057-a6d694cd6afd","added_by":"auto","created_at":"2025-12-10 15:45:13","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":217331,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in respiratory exchange ratio (RER) during exercise and recovery phase.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/b86be1843f4c4837b94bfc4f.png"},{"id":97900219,"identity":"8fd66629-8cbb-4cda-9ea7-bdeb3db245ab","added_by":"auto","created_at":"2025-12-10 15:45:18","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":298773,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in fat oxitadion percentage (FAT%) during exercise and recovery phase.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/e4254191be0f7d0a5e159629.png"},{"id":97882835,"identity":"6002eddf-7300-4fb9-8c9b-f4156fbc8008","added_by":"auto","created_at":"2025-12-10 12:45:21","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":220079,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in carbonhydrate oxidation percentage (CHO%) during exercise and recovery phase.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/8dd41d4a887b64a06acfd07f.png"},{"id":97903471,"identity":"263bd543-bf26-4c8a-8b97-c7eedc385c15","added_by":"auto","created_at":"2025-12-10 15:55:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1544188,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8279716/v1/b8f6688b-6e0c-4b4f-a3b9-d130ec7271c3.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"The Effect of FTO rs9939609 Gene Polymorphism on Exercise-Induced Fat Oxidation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe continuity of anabolic and catabolic processes in the body requires energy. This energy is provided through the oxidation of nutrients in the cells. Carbohydrates (CHO) and fat are the most essential energy sources for the body, playing a critical role in meeting energy demands. While numerous factors influence energy needs, one of the most significant is physical activity. The energy required during exercise varies depending on the intensity, duration, type of exercise, and an individual's fitness level. The rate of substrate oxidation during physical activity is affected by various factors such as age, gender, body composition, exercise duration, exercise mode, diet, and training status[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003eFat oxidation rate is regulated by multiple variables, including nutrition, muscle glycogen content, hormones, and an individual's fitness status. However, one of the most critical determinants is exercise intensity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Maximal oxygen consumption capacity (VO\u003csub\u003e2\u003c/sub\u003emax) is one of the primary references for defining exercise intensity. Exercises at approximately 65% of VO\u003csub\u003e2\u003c/sub\u003emax or below are classified as light to moderate intensity, whereas those above 65% are considered high-intensity exercises. It is well known that fat oxidation rates reach their highest levels during light to moderate-intensity exercise, but as intensity increases beyond this level, the amount of oxidized fat decreases[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] .Additionally, repeated exercise performed in two sessions has been found to result in higher fat oxidation compared to a single continuous session [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Fat oxidation rate and quantity vary depending on several factors such as nutrition, hormones, body glycogen content, and exercise [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In recent years, the role of genetic factors in obesity, fat accumulation, and fat oxidation has garnered increasing interest.\u003c/p\u003e\u003cp\u003eGenome-wide association studies (GWAS) have reliably demonstrated that SNPs located in the first intron of the FTO gene are strongly associated with increased BMI and fat accumulation across different ages and populations [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Several single nucleotide polymorphisms (SNPs) within the FTO gene have been linked to increased body mass index (BMI), waist circumference, total body mass, and fat mass levels[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. A recent study found that the FTO rs9939609 polymorphism is associated with maximal fat oxidation (in both absolute and relative values) regardless of gender and BMI [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe FTO gene, which was the first obesity-susceptibility gene discovered through GWAS in European individuals with type 2 diabetes, is located on chromosome 16, in the 16q12.2 region. This gene is highly expressed in the hypothalamus, pituitary, and adrenal glands, which are involved in body weight regulation and satiety. Various variants of the FTO gene have been shown to play a regulatory role in food intake control and energy balance [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The obesity-risk variant of the FTO rs9939609 polymorphism has been associated with increased appetite and higher energy intake in adults[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdults carrying the A allele of the FTO rs9939609 gene have been found to have higher body weight and BMI compared to those carrying the T allele. Individuals who are homozygous for the obesity-risk A allele have been reported to have a 1.7-fold higher risk of obesity compared to those who are homozygous for the lower-risk T allele [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, individuals with the TT genotype have been found to have significantly higher hunger and general appetite levels than those with the AT genotype [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, AT carriers have demonstrated lower fat oxidation values compared to TT genotypes. The presence of the TT allele in the FTO rs9939609 gene appears to serve as a protective factor against obesity and cardiometabolic diseases by contributing to better metabolic capacity and flexibility [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eStudies on the effect of the FTO rs9939609 gene polymorphism on exercise-induced fat oxidation are rather limited. Although numerous factors influence fat oxidation, the role of genetic composition in this process has not been fully elucidated. Therefore, determining the impact of the FTO rs9939609 polymorphism on fat oxidation during and after exercise may contribute to the development of individualized exercise and dietary strategies. The findings of this research could guide the development of new approaches for the prevention and treatment of obesity and metabolic diseases.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eStudy Population and Sample\u003c/p\u003e\u003cp\u003eThe study included 45 young adult male volunteers aged between 20 and 30 years, who had no health-related restrictions preventing them from exercising and had not engaged in regular physical activity in the past three years (sedentary). Prior to the study, approval was obtained from the Non-Interventional Clinical Research Ethics Committee of Ordu University Health Sciences Institute (Approval No: 2024/85). The exercise protocol of the study was conducted in the Performance Laboratory of Ordu University Faculty of Sports Sciences. All participants were informed about the study, including potential benefits and risks. Written informed consent was obtained in accordance with the Helsinki Declaration [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eDetermination of Body Weight\u003c/p\u003e\u003cp\u003eThe participants\u0026rsquo; physical characteristics were determined by measuring their height and weight. Height measurements were taken using a stadiometer (Holtain Ltd., Crymych, UK) while participants stood barefoot with their heads upright. Body weight was measured using an electronic scale (Seca 700; Seca GmbH, Hamburg, Germany).\u003c/p\u003e\u003cp\u003eIndirect Calorimetry\u003c/p\u003e\u003cp\u003eA portable gas analyzer (Cosmed K5, Cosmed, Rome, Italy) was used in the study. Prior to each test, room air calibration, reference gas calibration (with a gas mixture of 16% O\u003csub\u003e2\u003c/sub\u003e and 5% CO\u003csub\u003e2\u003c/sub\u003e), delay calibration, and turbine calibration were performed. Once the participant was ready, the analyzer was securely attached to allow free movement. Respiratory parameters were recorded using specialized software, and fat and carbohydrate oxidation rates were calculated using the following stoichiometric equations from Frayn (1983)[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eCarbohydrate oxidation\u0026thinsp;=\u0026thinsp;4.55 \u0026times; VCO\u003csub\u003e2\u003c/sub\u003e \u0026ndash; 3.21 \u0026times; VO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eFat oxidation\u0026thinsp;=\u0026thinsp;1.67 \u0026times; VO\u003csub\u003e2\u003c/sub\u003e \u0026ndash; 1.67 \u0026times; VCO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThe percentage of fat and carbohydrate oxidation during exercise tests was calculated using the formula proposed by Dumortier et al. (2005):\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e% Fat = [(1-RER)/0.29] \u0026times; 100\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e\u0026bull; % CHO = [(RER-0.71)/0.29] \u0026times; 100\u003c/h2\u003e\u003cp\u003eDetermination of Maximal Aerobic Power (MaxVO\u003csub\u003e2\u003c/sub\u003e) and Maximal Fat Oxidation Rate\u003c/p\u003e\u003cp\u003eAfter an adequate warm-up, participants performed an incremental treadmill test on a Woodway treadmill. Fat oxidation rates were measured both during exercise and for 15 minutes post-exercise (Recovery) to evaluate metabolic flexibility and recovery response using a portable gas analyzer (K5, Cosmed, Rome, Italy).\u003c/p\u003e\u003cp\u003eModified Bruce Protocol\u003c/p\u003e\u003cp\u003eThe Bruce protocol began with the collection of baseline values using the gas analyzer. After a standard warm-up, the test started at 1.7 mph with a 10% incline. Every three minutes, the speed and incline were increased until the participant reached exhaustion. The test consisted of seven stages, with corresponding incline, speed, and duration values presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eModified Bruce Protocol\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLevel\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSpeed (km/h)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIncline (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eDuration (min)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTotal Duration (min)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eGenetic Analysis\u003c/p\u003e\u003cp\u003eGenomic DNA extraction was performed using the DiaRex\u0026reg; Whole Blood Genomic DNA Extraction Kit (Cat. No: BLD-5295, Diagen, Ankara). The process involved lysis, proteinase K digestion, ethanol precipitation, and column-based purification to obtain high-quality genomic DNA. The nucleic acid concentrations of the extracted genomic DNA samples were measured using a Colibri Microvolume Spectrometer (Titertek-Berthold, Germany). Real-time PCR was used to analyze specific FTO rs9939609 gene regions. The primers were synthesized (Biomers, Germany) and reactions were performed using TaqProbe 2X qPCR MasterMix (Sansifast, UK). PCR amplification was carried out using a BioRad CFX-96 system.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eData Analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics 26.0. The Shapiro-Wilk test was used to assess normality. Descriptive statistics were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Independent Sample t-tests (for two groups) and one-way ANOVA (for three groups) were conducted. Chi-square tests (χ\u0026sup2;) were used to evaluate Hardy-Weinberg equilibrium. Statistical significance was set at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThe genotype distribution for the FTO rs9939609 polymorphism was tested for Hardy-Weinberg Equilibrium (HWE), yielding a p-value of 0.862. Since p\u0026thinsp;\u0026gt;\u0026thinsp;0.05, the observed genotype frequencies did not significantly deviate from HWE expectations, indicating that the sample population follows normal Mendelian inheritance patterns and that no selection bias or population stratification was present.\u003c/p\u003e\u003cp\u003eThe baseline characteristics of participants, categorized by FTO rs9939609 genotype, are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. No significant differences were observed among genotype groups for age (p\u0026thinsp;=\u0026thinsp;0.406), height (p\u0026thinsp;=\u0026thinsp;0.929), weight (p\u0026thinsp;=\u0026thinsp;0.624), or BMI (p\u0026thinsp;=\u0026thinsp;0.620). The mean age of participants was 23.26\u0026thinsp;\u0026plusmn;\u0026thinsp;2.32 years, and their average BMI was 24.43\u0026thinsp;\u0026plusmn;\u0026thinsp;4.17 kg/m\u0026sup2;. Although slight variations were noted, with the TA genotype group showing the highest mean BMI (25.06\u0026thinsp;\u0026plusmn;\u0026thinsp;4.97) and the AA group having the lowest (23.42\u0026thinsp;\u0026plusmn;\u0026thinsp;1.89), these differences did not reach statistical significance (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eDuring exercise, TT vs. AA\u0026thinsp;+\u0026thinsp;AT groups had nearly identical metabolic values. For instance, mean RER was 0.845 in TT vs. 0.839 in the AA\u0026thinsp;+\u0026thinsp;AT group, and fat oxidation averaged 53.1 vs. 56.5 units, respectively \u0026ndash; differences that were not statistically significant (p\u0026thinsp;=\u0026thinsp;0.505 for RER; p\u0026thinsp;=\u0026thinsp;0.339 for fat)​. Carbohydrate use was also similar (46.9 vs 43.5 units, p\u0026thinsp;=\u0026thinsp;0.331)​. In the recovery phase, the two groups remained very close: RER 0.997 (TT) vs. 0.994 (AA\u0026thinsp;+\u0026thinsp;AT, p\u0026thinsp;=\u0026thinsp;0.911), fat oxidation 34.8 vs. 35.9 (p\u0026thinsp;=\u0026thinsp;0.804), and CHO oxidation 65.45 vs. 64.05 (p\u0026thinsp;=\u0026thinsp;0.755) no meaningful differences (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eEvaluation of RER, Fat Oxidation, and Carbohydrate Oxidation Based on the Dominant Model (TT vs. TA\u0026thinsp;+\u0026thinsp;TT)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDominant Model\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMean\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003esd\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003et\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e\u003cb\u003eDuring Exercise\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eRER\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e,845\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,044\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,672\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,505\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTA\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e,839\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,045\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eFAT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e53,10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,595\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-,966\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,339\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTA\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e56,54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,669\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eCHO\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e46,94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,509\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,984\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,331\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTA\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e43,45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,669\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e\u003cb\u003eIn Recovery\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eRER\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e,9971\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,08793\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,911\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTA\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e,9942\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,08335\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eFAT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e34,8196\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15,1580\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-,250\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,804\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTA\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e35,9230\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13,8974\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eCHO\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e65,4510\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15,4076\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,315\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,755\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTA\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e64,0504\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13,8983\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cb\u003e*p\u0026thinsp;\u0026lt;\u0026thinsp;0,05\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe mean RER value for individuals with the AA genotype was 0.812\u0026thinsp;\u0026plusmn;\u0026thinsp;0.035, whereas for those with the AT\u0026thinsp;+\u0026thinsp;TT genotype, it was 0.849\u0026thinsp;\u0026plusmn;\u0026thinsp;0.044. During exercise, the t-test revealed a statistically significant difference between the two groups (t =-2.536; p\u0026thinsp;=\u0026thinsp;0.026), with the AT\u0026thinsp;+\u0026thinsp;TT genotype group having a significantly higher RER value than the AA genotype group. At recovery, AA also showed a lower mean RER (0.947 vs. 1.006 for AT\u0026thinsp;+\u0026thinsp;TT), though this gap did not reach significance (p\u0026thinsp;=\u0026thinsp;0.075)​ (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eEvaluation of RER, Fat Oxidation, and Carbohydrate Oxidation Based on the Recessive Model (AA vs. AT\u0026thinsp;+\u0026thinsp;TT)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRecessive Model\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMean\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003esd\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003et\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e\u003cb\u003eDuring Exercise\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eRER\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e,812\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-2,536\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,\u003cb\u003e026*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e,849\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,044\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eFAT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e64,507\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7,713\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,389\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,\u003cb\u003e004*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e53,325\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,446\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eCHO\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e35,494\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7,716\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-3,398\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,\u003cb\u003e004*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e46,695\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e11,409\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e\u003cp\u003e\u003cb\u003eIn Recovery\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eRER\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e,9474\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,09247\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-1,820\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,075\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,0057\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e,07979\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eFAT\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e44,4624\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16,7125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e2,033\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,\u003cb\u003e048*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e33,5697\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13,0897\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e\u003cb\u003eCHO\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e55,5376\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16,7125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e-2,038\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e,\u003cb\u003e048*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAT\u0026thinsp;+\u0026thinsp;TT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e66,5345\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13,2118\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003e\u003cb\u003e*p\u0026thinsp;\u0026lt;\u0026thinsp;0,05\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIndividuals with the AA genotype consistently exhibited higher fat oxidation rates than AT\u0026thinsp;+\u0026thinsp;TT. In the exercise phase, the AA group oxidized on average 64.507\u0026thinsp;\u0026plusmn;\u0026thinsp;7.713 units of fat vs. 53.325\u0026thinsp;\u0026plusmn;\u0026thinsp;11.446 in the AT\u0026thinsp;+\u0026thinsp;TT group \u0026ndash; a significant increase in the AA genotype (p\u0026thinsp;=\u0026thinsp;0.004)​ Notably, this difference persisted in the recovery phase: AA genotype fat oxidation averaged 44.46 vs. 33.57 for AT\u0026thinsp;+\u0026thinsp;TT, indicating 33% greater fat use by AA (this difference was also significant, p\u0026thinsp;=\u0026thinsp;0.048) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.).\u003c/p\u003e\u003cp\u003eThe AA genotype showed lower carbohydrate oxidation compared to AT\u0026thinsp;+\u0026thinsp;TT, complementing their higher fat use. During exercise, AA individuals oxidized 35.494\u0026thinsp;\u0026plusmn;\u0026thinsp;7.716 units of CHO on average, whereas the AT\u0026thinsp;+\u0026thinsp;TT group oxidized 46.695\u0026thinsp;\u0026plusmn;\u0026thinsp;11.409 \u0026ndash; a significant difference (p\u0026thinsp;=\u0026thinsp;0.004). At recovery, AA continued to use less carbohydrate (55.54 vs. 66.53 in AT\u0026thinsp;+\u0026thinsp;TT, p\u0026thinsp;=\u0026thinsp;0.048)​ (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.).\u003c/p\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the respiratory exchange ratio (RER) values during the exercise and recovery protocols. The analysis indicated that the AA genotype group exhibited significantly lower RER values compared to the AT\u0026thinsp;+\u0026thinsp;TT group during the exercise session (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the fat oxidation rates for both groups. The data showed that individuals with the AA genotype achieved significantly higher fat oxidation rates than the T-allele carriers (AT\u0026thinsp;+\u0026thinsp;TT) during both the exercise and recovery periods (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Conversely, carbohydrate oxidation rates, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e4\u003c/span\u003e, were significantly lower in the AA genotype group compared to the AT\u0026thinsp;+\u0026thinsp;TT group during the exercise protocol (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). A similar trend of lower carbohydrate oxidation in the AA group persisted during the recovery phase (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results of this study add to a mixed body of literature on FTO polymorphisms and substrate oxidation during exercise. Some prior studies have reported little to no effect of the FTO rs9939609 variant on fuel utilization. For example, Garc\u0026iacute;a-Pastor et al. found no significant differences in maximal fat oxidation (MFO) during exercise across TT, AT, and AA genotypes (MFO 0.35\u0026ndash;0.37 g/min in all groups, p\u0026thinsp;=\u0026thinsp;0.702)​. Their work concluded a \u0026ldquo;lack of genetic association\u0026rdquo; between FTO genotype and fat-burning capacity in healthy young adults​. This aligns with other research suggesting that FTO\u0026rsquo;s influence on energy expenditure may be modest. Danaher et al. also observed similar metabolic flexibility between FTO genotypes in response to diet, implying minimal differences in substrate use under acute challenges​ [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e\u003cp\u003eHowever, our findings diverge from studies that do report genotype-dependent differences. Notably, Ponce-Gonz\u0026aacute;lez et al. observed that individuals carrying the risk A allele had altered exercise fuel metabolism​ In their study, heterozygotes (AT) showed lower fat oxidation rates during exercise compared to TT homozygotes. Interestingly, those authors noted that homozygous AA individuals did not have further reductions in fat use \u0026ndash; in fact, AA participants\u0026rsquo; fat oxidation was comparable to TT subjects​. This unexpected pattern (TT\u0026thinsp;\u0026gt;\u0026thinsp;AT, with AA\u0026thinsp;\u0026asymp;\u0026thinsp;TT in fat utilization) suggests a non-linear or threshold effect of the FTO variant, rather than a simple dose-response. Our results lend support to a recessive model of effect: we found that only AA homozygotes differed significantly from others, with higher fat oxidation and lower RER than AT/TT. This contrasts with the hypothesis that obesity-risk A allele necessarily impairs fat burning​. Instead, our AA group oxidized more fat (and less carbohydrate) during exercise, an outcome that is opposite to what one might predict for an \u0026ldquo;obesity-prone\u0026rdquo; genotype. Such discrepancies underscore that the relationship between FTO genotype and substrate oxidation is complex and may depend on study design, population, or statistical models. Indeed, the FTO gene has been widely linked to BMI and adiposity​, but its impact on exercise metabolism appears subtler and context-dependent. Consistent with our findings, one recent report noted that associations of FTO with metabolic traits were most evident when comparing AA vs. T-allele carriers (recessive model), even though no overall genotype effect on MFO was seen​ [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Thus, while our study\u0026rsquo;s observation (enhanced fat oxidation in AA genotype) is somewhat atypical, it highlights the need to consider different genetic models and suggests that previous null findings could mask effects present only in homozygous risk carriers.\u003c/p\u003e\u003cp\u003eSeveral biological mechanisms might explain how the FTO rs9939609 variant influences fuel selection during exercise. One possibility involves differences in insulin sensitivity and metabolic flexibility. The A allele of rs9939609 has been associated with elevated fasting insulin and glucose levels, indicating a trend toward insulin resistance in carriers [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]​. Insulin resistance could limit muscular uptake and oxidation of glucose, forcing greater reliance on fatty acids for energy during exercise. In line with this, our AA participants (who likely have the greatest genetic predisposition to insulin resistance) showed the lowest carbohydrate use and RER. Impaired insulin signaling in muscle can blunt carbohydrate oxidation, effectively \u0026ldquo;pushing\u0026rdquo; metabolism toward fat, especially at moderate intensities. Interestingly, \u003cem\u003ein vivo\u003c/em\u003e muscle studies support this interpretation: Grunnet et al. reported that homozygous A carriers exhibit higher hepatic insulin resistance along with faster phosphocreatine recovery in oxidative muscle fibers after exercise​. A faster PCr recovery half-time suggests enhanced mitochondrial oxidative capacity or efficiency in regenerating ATP. This paradoxical finding \u0026ndash; risk-allele carriers with seemingly better muscle oxidative recovery \u0026ndash; could reflect an adaptive metabolic response or muscle fiber-type differences. Indeed, skeletal muscle characteristics may play a role. A genetic study by Guilherme et al. noted that the A allele is associated with a lower proportion of slow-twitch (type I) oxidative fibers in muscle. Typically, having fewer type I fibers would reduce fat oxidation capacity (since type I fibers are highly fat-adaptive), potentially making carriers more reliant on glycolytic (carbohydrate-fueled) pathways. Yet, in our untrained sample, the AA group still oxidized more fat; this might indicate that other compensatory mechanisms (such as those related to insulin or mitochondria) outweighed fiber-type influences, or simply that our AA subjects, despite genetic risk, had not developed the phenotypic traits (e.g. lower oxidative capacity) often seen in overweight individuals. It is also plausible that FTO genotype affects hormonal responses that modulate substrate use. FTO is highly expressed in the brain\u0026rsquo;s energy-regulation centers, and A alleles have been linked to higher circulating ghrelin (hunger hormone) and appetite. While appetite per se does not acutely alter exercise metabolism, chronically higher caloric intake could lead to differences in body composition or muscle metabolism over time. We controlled for BMI (our groups were weight-matched), but subtle differences in muscle lipid content or enzyme levels could exist. Additionally, FTO-related genetic variation might alter expression of genes involved in mitochondrial function. Research has shown that overexpression of FTO in muscle cells can induce lipid accumulation and mitochondrial dysfunction​ (Bravard et al. 2011). If risk-allele carriers have higher FTO activity in muscle, they might experience changes in how substrates are oxidized \u0026ndash; for instance, accumulating intramuscular fat that could paradoxically serve as fuel during exercise. Another mechanism to consider is the role of FTO in adipose tissue. The intronic FTO variant has been found to influence adipocyte browning through downstream targets IRX3/IRX5, affecting whole-body energy expenditure. The A allele tends to reduce basal lipolysis \u0026ndash; in vitro studies showed 22% lower spontaneous fat cell lipolysis in A carriers compared to TT​ and promotes fat storage in adipocytes​ (Wahlen et al. 2008). At face value, reduced baseline lipolysis would suggest less fatty acid availability for oxidation. However, during exercise, catecholamine-stimulated lipolysis was reported to be similar between genotypes​, meaning that under exercise stress, A carriers can mobilize fat as effectively as T carriers. Our data might indicate that once mobilized, those fatty acids were readily oxidized by AA individuals. It is conceivable that the metabolic inflexibility often attributed to the FTO risk genotype (such as difficulty switching between fuels) manifests in a nuanced way: in the fasted, moderate-intensity exercise state, AA individuals might remain in a fat-burning mode to a greater extent, whereas T-allele carriers shift to carbohydrates more readily. In summary, the FTO rs9939609 variant likely exerts its effects on exercise metabolism via a combination of factors \u0026ndash; insulin dynamics, muscle fiber composition, mitochondrial function, and adipose tissue biology \u0026ndash; rather than a single pathway. Further mechanistic studies (e.g. muscle biopsies and fuel utilization tests across varying conditions) are warranted to pinpoint how this gene alters the interplay between carbohydrate and fat metabolism.\u003c/p\u003e\u003cp\u003eOur findings, if confirmed, could have noteworthy implications for personalized exercise recommendations and metabolic health strategies. One immediate consideration is in the context of obesity prevention and weight management. Carriers of the FTO A allele are known to have a higher propensity for weight gain, largely due to increased appetite and caloric intake. Regular exercise is often recommended to mitigate this risk, and our results reinforce that advice. In fact, prior research shows that an active lifestyle can attenuate the BMI-increasing effect of FTO risk variants by roughly 27\u0026ndash;30% [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. For individuals with the high-risk AA genotype, exercise might be doubly important \u0026ndash; not only to burn calories, but also to improve or maintain metabolic flexibility. The observation that AA carriers in our study oxidize fat well at moderate intensity suggests they could leverage steady-state aerobic exercise as an effective way to utilize excess fat stores. Exercise programs emphasizing endurance activities (e.g. cycling, running at moderate intensity) might align with their intrinsic tendency to burn fat, potentially aiding in preventing fat accumulation. On the other hand, the lower reliance on carbohydrates in AA individuals might indicate a need to improve their capacity for high-intensity, glycolytic work. Thus, a balanced program that includes some high-intensity training could help risk-allele carriers enhance carbohydrate metabolism and insulin sensitivity, counteracting any predisposition toward insulin resistance.\u003c/p\u003e\u003cp\u003eFuture research should include diverse populations to see if our findings hold across genders, age ranges, and fitness levels. Third, the study design was cross-sectional, measuring acute exercise substrate oxidation at a set intensity. We did not assess a full range of intensities or the time-course of adaptation. It would be informative to examine metabolic responses over a spectrum of exercise intensities (from low to high) to determine if genotype effects are more pronounced at particular workloads or during recovery. Measuring the entire fat oxidation curve and the point of maximal fat oxidation (Fatmax) for each genotype group could reveal nuances that a single-intensity measurement might miss. Additionally, we relied on indirect calorimetry equations to estimate fat and CHO oxidation, which, while standard, are subject to assumptions (e.g. negligible protein oxidation, steady-state conditions). Any systematic error in these estimates would affect all participants similarly, but it is something to consider in interpreting absolute values. We also did not directly measure potential mediators such as insulin levels, free fatty acid concentrations, or muscle glycogen content. Including such physiological measurements could help explain why genotypes differ in RER.\u003c/p\u003e\u003cp\u003eThe present study has certain limitations that should be noted. Primarily, the sample size for the homozygous allele (AA) group was relatively small (n\u0026thinsp;=\u0026thinsp;8). However, the observation of statistically significant differences in substrate oxidation, despite this limited sample size, suggests that the physiological effect of the genotype is robust and pronounced. Therefore, while replication in larger cohorts is necessary for broader generalizability, the findings presented here provide valuable and strong evidence regarding the metabolic impact of the FTO variant. Secondly, this study focused exclusively on the FTO rs9939609 polymorphism; given the polygenic nature of metabolic regulation, future studies should address the combined effects of multiple genetic variants on exercise metabolism.\u003c/p\u003e\u003cp\u003eOverall, having one A allele (heterozygous AT) did not significantly alter fuel utilization compared to TT. All comparisons between the TT genotype and the combined non-TT group showed p\u0026thinsp;\u0026gt;\u0026thinsp;0.05, indicating no statistically significant metabolic difference. In conclusion, while our study provides novel insights into FTO rs9939609 and exercise fuel use, it raises as many questions as it answers. By addressing the limitations above, future work can clarify the role of FTO in exercise metabolism and determine how to best apply this knowledge for improving health and performance. The significance of our findings lies in contributing to a more nuanced understanding of \u0026ldquo;obesity genes\u0026rdquo;: rather than simply predisposing one to weight gain, FTO genotype may subtly shape how the body derives energy during physical activity an insight that could eventually be leveraged in personalized nutrition and exercise guidelines for more effective obesity prevention and fitness optimization.​\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution Statement:\u003c/h2\u003e\u003cp\u003eAll authors contributed to the conceptualization, design, and literature review of the study. The identification of participants, providing information about the study, obtaining informed consent, inclusion in the study, and collection of the necessary documents were carried out by A.E., N.A. and G.I. The design of primers/probes required for the study, genetic analyses, and appropriate sample collection from participants under suitable conditions were performed by C.D. All authors contributed to the writing of the manuscript and its translation into English.\u003c/p\u003e\u003ch2\u003eEthics approval:\u003c/h2\u003e\u003cp\u003ePrior to the study, approval was obtained from the Non-Interventional Clinical Research Ethics Committee of Ordu University Health Sciences Institute (Approval No: 2024/85). The exercise protocol of the study was conducted in the Performance Laboratory of Ordu University Faculty of Sports Sciences. All participants were informed about the study, including potential benefits and risks. Written informed consent was obtained in accordance with the Helsinki Declaration.\u003c/p\u003e\u003ch2\u003eCompeting Interests:\u003c/h2\u003e\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose\u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e\u003cp\u003eThis research was supported by the Ordu University Scientific Research Project Office as a master's thesis under project number B-2414.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e\u003cp\u003eThe authors extend their heartfelt appreciation to all volunteers who took part in this study. The participants' engagement, commitment, and valuable contributions played a significant role in the successful execution of the research.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eIpekoğlu G, Balcı ŞS. Comparison between continuous and intermittent submaximal exercise at the intensity of maximal fat oxidation. J Hum Sci. 2016; 13:4604\u0026ndash;4612.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRomijn JA, Coyle EF, Sidossis LS, Gastaldelli A, Horowitz JF, Endert E, Wolfe RR. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol. 1993; 265:E380\u0026ndash;391.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAchten J, Gleeson M, Jeukendrup AE. Determination of the exercise intensity that elicits maximal fat oxidation. Med Sci Sports Exerc. 2002; 34:92\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGoto K, Ishii N, Mizuno A, Takamatsu K. Enhancement of fat metabolism by repeated bouts of moderate endurance exercise. J Appl Physiol. 2007; 102:2158\u0026ndash;2164.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePurdom T, Kravitz L, Dokladny K, Mermier C. Understanding the factors that effect maximal fat oxidation. J Int Soc Sports Nutr. 2018; 15:3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFrayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316:889\u0026ndash;894.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eScuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J, et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genet. 2007; 3:e115.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePonce-Gonzalez JG, Martinez-Avila A, Velazquez-Diaz D, Perez-Bey A, Gomez-Gallego F, Marin-Galindo A, et al. Impact of the FTO gene variation on appetite and fat oxidation in young adults. Nutrients. 2023; 15:2196.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarginean CO, Marginean C, Melit LE. New insights regarding genetic aspects of childhood obesity: a minireview. Front Pediatr. 2018; 6:271.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSpeakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity. 2008; 16:1961\u0026ndash;1965.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWorld Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013; 310:2191\u0026ndash;2194.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFrayn KN. Calculation of substrate oxidation rates in vivo from gaseous exchange. J Appl Physiol Respir Environ Exerc Physiol. 1983; 55:628\u0026ndash;634.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a-Pastor T, Mu\u0026ntilde;oz-Puente I, P\u0026eacute;rez-Pelayo M, P\u0026uacute;a I, Roberts JD, Del Coso J. Maximal Fat Oxidation During Exercise in Healthy Individuals: Lack of Genetic Association with the FTO rs9939609 Polymorphism. Genes (Basel). 2024;16(1):4.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGrunnet LG, Brons C, Jacobsen S, Nilsson E, Astrup A, Hansen T, et al. Increased recovery rates of phosphocreatine and inorganic phosphate after isometric contraction in oxidative muscle fibers and elevated hepatic insulin resistance in homozygous carriers of the A-allele of FTO rs9939609. J Clin Endocrinol Metab. 2009; 94:596\u0026ndash;602.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKilpelainen TO, Qi L, Brage S, Sharp SJ, Sonestedt E, Demerath E, et al. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med. 2011; 8:e1001116.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-nutrition","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejcn","sideBox":"Learn more about [European Journal of Clinical Nutrition](http://www.nature.com/ejcn/)","snPcode":"41430","submissionUrl":"https://mts-ejcn.nature.com/cgi-bin/main.plex","title":"European Journal of Clinical Nutrition","twitterHandle":"@ejcneditor","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"FTO rs9939609, genetic polymorphism, fat oxidation, carbohydrate oxidation","lastPublishedDoi":"10.21203/rs.3.rs-8279716/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8279716/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe FTO rs9939609 polymorphism is well-studied for obesity and metabolism, but its effect on exercise-induced substrate oxidation remains unclear. This study aimed to examine the impact of the FTO rs9939609 polymorphism on fat oxidation (FAT), carbohydrate oxidation (CHO), and respiratory exchange ratio (RER) during and after exercise in sedentary young adult males.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eA total of 45 male participants were recruited and genotyped for FTO rs9939609. Participants underwent an incremental treadmill exercise test, during which RER, FAT, and CHO oxidation rates were measured using indirect calorimetry. Substrate oxidation was assessed during both exercise and a 15-minute post-exercise recovery period. Data was analyzed according to recessive and dominant genetic models.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe AA genotype group exhibited a significantly lower RER during compared to the AT\u0026thinsp;+\u0026thinsp;TT group, indicating a greater reliance on fat oxidation. Similarly, AA carriers had higher fat oxidation than AT\u0026thinsp;+\u0026thinsp;TT, while carbohydrate oxidation was significantly lower in AA compared to AT\u0026thinsp;+\u0026thinsp;TT. This trend persisted in the post-exercise recovery phase, with AA individuals maintaining higher fat oxidation and lower RER, though differences were less pronounced.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe findings suggest that the FTO rs9939609 polymorphism influences substrate oxidation in a recessive manner. AA genotype carriers oxidize fat over carbohydrates during moderate-intensity exercise and post-exercise recovery, while individuals with at least one T allele exhibit higher carbohydrate utilization. These results imply that genetic factors may play a role in metabolic responses to exercise. Future studies with larger, diverse populations and longitudinal training interventions are needed to confirm these findings.\u003c/p\u003e","manuscriptTitle":"The Effect of FTO rs9939609 Gene Polymorphism on Exercise-Induced Fat Oxidation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-10 12:45:14","doi":"10.21203/rs.3.rs-8279716/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"This content is not available.","date":"2026-01-19T15:35:02+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-01-19T13:01:52+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2025-12-08T00:18:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-05T10:49:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-05T10:49:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Clinical Nutrition","date":"2025-12-04T13:10:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-clinical-nutrition","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"ejcn","sideBox":"Learn more about [European Journal of Clinical Nutrition](http://www.nature.com/ejcn/)","snPcode":"41430","submissionUrl":"https://mts-ejcn.nature.com/cgi-bin/main.plex","title":"European Journal of Clinical Nutrition","twitterHandle":"@ejcneditor","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3f2a0cfc-55e0-4446-990f-331359abc3ba","owner":[],"postedDate":"December 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":59235633,"name":"Health sciences/Biomarkers"},{"id":59235634,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-12-10T12:45:14+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-10 12:45:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8279716","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8279716","identity":"rs-8279716","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}