Methodology

A comprehensive search strategy was implemented to identify relevant studies published between January 2008 and January 2025. Literature searches were conducted using PubMed, Google Scholar, and ScienceDirect, and the retrieved information was synthesised into a structured narrative review. The following key words and their combinations were used: nutrigenetics, nutrigenetic testing, precision nutrition, obesity, body composition, FTO gene, FTO variant, polygenic obesity, personalized weight management, dietary interventions, high-calorie foods, high-protein diet, and weight loss. Boolean operators (AND/OR) were applied to refine searches and ensure comprehensive retrieval of relevant literature. To ensure a focused exploration of the impact of the FTO gene on polygenic obesity and the role of precision nutrition in personalised weight management, studies were included if they examined the genetic influences of obesity, particularly the role of the FTO gene, and/or investigated gene–diet interactions and personalised dietary interventions for obesity management, and/or explored the FTO gene’s influence on appetite regulation and energy expenditure, and/or assessed the potential of precision nutrition for personalised obesity management, and were primary research studies, including clinical studies, GWAS, randomised controlled trials (RCTs), and intervention studies. Only studies published in English were included, to ensure consistency in interpretation and analysis. The selection process followed a structured approach to identify and evaluate relevant studies. First, titles and abstracts were screened to determine alignment with the review’s aim. Studies meeting the initial criteria underwent a full-text review to assess methodological rigour, relevance, and contribution to the understanding of FTO gene-driven obesity and precision nutrition interventions. The synthesised evidence was organised thematically to provide a comprehensive narrative on how nutrigenetics informs personalised weight management strategies, highlighting key findings, emerging trends, and research gaps.

Fat mass and obesity-associated gene (FTO): a key player in polygenic obesity

The FTO gene, located on chromosome 16q12.2, encodes the fat mass and obesity-associated protein, which is involved in energy homeostasis, appetite regulation, and body mass regulation^{(Reference Price, Li and Zhao11)}. Notably, the obesity-associated single nucleotide polymorphisms (SNPs) within FTO are not randomly distributed but are highly clustered within the first and second introns of the gene. These intronic variants are in strong linkage disequilibrium, meaning that many commonly studied SNPs (e.g., FTO rs9939609, FTO rs1421085, FTO rs1558902) are highly correlated and often tag the same underlying genetic signal. This genomic architecture explains why multiple FTO SNPs have been repeatedly associated with obesity-related traits across studies^{(Reference Loos and Yeo12)}.

The FTO gene can experience both homozygous and heterozygous types of mutations that lead to polygenic obesity. As a member of the AlkB-related non-heme iron and 2-oxoglutarate-dependent oxygenase superfamily, the FTO protein is involved in the demethylation of nucleic acids, particularly mRNA, which influences gene expression related to adipogenesis, fat storage, and energy intake⁽¹³⁾. The gene’s involvement in demethylation processes suggests that it may modulate the expression of other genes involved in metabolic pathways, but the precise biological pathways remain under investigation. This gap in knowledge highlights the need for further research to elucidate the molecular mechanisms by which FTO influences obesity.

Variants of the FTO gene have been strongly associated with an increased risk of obesity, making it one of the most studied genes in the context of polygenic obesity. The FTO gene has high and low obesity risk variants. Each person inherits two copies, one from each parent. Inheriting two high-risk copies increases obesity risk by around 70%⁽¹⁴⁾. FTO gene variants (such as FTO rs9939609) are strongly associated with increased BMI and obesity. These variants are linked to increased food intake and preference for energy-dense, high-calorie foods. The mechanism involves the regulation of hypothalamic neurons, which control hunger and satiety^{(Reference Haupt, Thamer and Staiger15,Reference Church, Lee and Bagg16)} . In individuals with risk variants, FTO expression is altered, leading to dysregulated appetite signalling, increased caloric intake, and, ultimately, weight gain.

Additionally, studies have shown that the FTO gene appears to influence the browning of adipose tissue, a process where white fat is converted into brown-like adipocytes, which affects energy expenditure and fat storage. Claussnitzer et al. demonstrated that a specific SNP in the FTO gene (FTO rs1421085) disrupts a conserved motif for the ARID5B repressor, leading to increased expression of IRX3 and IRX5. This shift promotes the development of white adipocytes over brown adipocytes, thereby reducing thermogenesis and increasing fat storage. The interaction between dietary components and FTO gene variants also plays a role in adipose tissue browning. Omega-3 fatty acids have been found to promote the browning of white adipose tissue (WAT), potentially counteracting the effects of FTO risk alleles^{(Reference Toth, Arianti and Shaw17)}. Since this variant shifts the balance from energy-burning brown adipocytes to energy-storing white adipocytes, heat production and fat-burning capacity are reduced. As a result, individuals with this variant are more prone to storing fat and have a reduced ability to metabolise it efficiently, contributing to obesity. These studies highlight how specific FTO variants, like FTO rs1421085, can directly impact metabolic processes and energy balance, emphasising the importance of understanding genetic influences on obesity and tailoring interventions accordingly. However, the exact mechanism of the FTO gene regulating body fat and body weight is under study^{(Reference Huang, Chen and Wang18)}.

A case-control study by Proença da Fonseca et al. examined the association of genetic polymorphisms with obesity class II or greater and related obesity traits in a Brazilian cohort of 501 participants. Results showed that the FTO rs17817449 TT genotype was significantly linked to severe obesity and distinct cytokine expression. Moreover, this study also revealed that individuals with severe obesity (cases group) were more likely to carry eight or more genetic risk alleles compared to those in the normal-weight control group^{(Reference Salum, Assis and Kopke19)}. The results indicated that a higher number of these obesity-related genetic variations were more common among people with severe obesity, suggesting a stronger genetic influence on their condition.

De Soysa et al. examined the association between FTO rs9939609 genotypes and appetite-related hormones in 96 adults with severe obesity and found that, for women with the AA genotype, having more body fat was linked to higher ghrelin levels compared to those with the TT or AT genotypes^{(Reference De Soysa, Langaas and Grill20)}. This suggests that body fat may influence hunger signals differently in people with certain FTO gene variations, which needs further study. Similarly, a recent study in the Journal of Lifestyle Genomics examined FTO gene SNP rs9939609’s association with appetite traits in people who are normal weight. It compared subjective appetite sensations, ghrelin and insulin levels, and dietary intake based on the FTO rs9939609 genotype. The study concluded that carriers of the A allele of FTO rs9939609 may have a stronger preference for foods with added sugars^{(Reference Madrigal-Juarez, Martínez-López and Sanchez-Murguia21)}. Supporting these findings, studies on adiposity-matched people who are normal weight demonstrated that AA carriers of FTO rs9939609 exhibit higher circulating acyl-ghrelin (AG) levels, attenuated postprandial appetite suppression, and altered neural responses to food cues in homeostatic and reward-related brain regions. Mechanistically, FTO was shown to regulate ghrelin expression via reduced m6A methylation of ghrelin mRNA, providing a direct link between FTO risk alleles and increased energy intake^{(Reference Karra, Daly and Choudhury22)}. In a randomised crossover study of 12 males with the AA genotype of FTO rs9939609 and 12 males with the TT genotype, participants completed a control (eight hours rest) and exercise (one hour at 70% peak oxygen uptake, seven hours rest) trial, with a fixed meal at 1.5 hours and an ad libitum buffet at 6.5 hours. AA genotype of FTO rs9939609 individuals showed lower baseline BChE (butyrylcholinesterase) activity, higher AG:DAG ratios, attenuated postprandial AG suppression, and greater ad libitum energy intake. Exercise increased BChE activity and suppressed AG and the AG:DAG ratio, effectively normalising the higher ghrelin profile in AA carriers of FTO rs9939609, though energy intake remained unchanged^{(Reference Dorling, Clayton and Jones23)}. These findings suggest that the FTO rs9939609 A allele influences appetite and energy intake through both hormonal and neural mechanisms, and that lifestyle interventions such as exercise may mitigate these genotype-related effects.

It has been revealed that the FTO gene’s influence on obesity is more complex than previously believed⁽²⁴⁾. These findings reveal the potential for precision nutrition to address the genetic and behavioural factors contributing to obesity. By tailoring dietary recommendations to an individual’s genetic profile, it may be possible to mitigate the effects of high-risk FTO variants. However, the implementation of such strategies requires robust evidence from large-scale, long-term studies to ensure their effectiveness and safety.

Role of precision nutrition in obesity management: a promising approach to personalised obesity management

Precision nutrition and nutrigenetics intersect by using genetic information to customise and personalise dietary guidance. As outlined in Figure 1, precision nutrition incorporates genomic data, alongside lifestyle, behaviour, and physiological factors, to develop personalised and universal guidelines for maintaining health, managing non-communicable diseases, and implementing health strategies^{(Reference Asghar and Khalid25)}.

Fig. 1.

The interplay between genetic background, biological, cultural, and environmental variations on personalised nutrition.

Unhealthy dietary patterns are associated with an increased risk of obesity. Associations between non-modifiable risk factors, such as genetic variations and obesity, may be modified by diet^{(Reference Livingstone, Brayner and Celis-Morales26)}. High intake of sugar-sweetened beverages, fried food, and a sedentary lifestyle are particular risk factors for obesity among adults and children due to their complex interaction with genetic variants associated with obesity^{(Reference Naureen, Miggiano and Aquilanti27)}.

In recent years, precision nutrition has emerged as a transformative approach to obesity management. By leveraging insights from an individual’s genetic makeup, healthcare providers can tailor dietary recommendations to optimise macronutrient composition, portion sizes, and specific dietary adjustments. This personalised strategy not only enhances the effectiveness of weight loss interventions but also improves long-term weight management outcomes^{(Reference Chao, Quigley and Wadden28)}.

As shown in Table 1, different FTO variants are associated with specific dietary patterns to help manage BMI and obesity risk. These findings highlight the growing importance of precision nutrition, which lies in its ability to move beyond a ‘one-size-fits-all’ approach to offering targeted interventions that align with an individual’s unique biological and genetic profile^{(Reference Yoon, Lee and Oh29)}. As research continues to uncover the complex interactions between genetics, diet, and lifestyle, precision nutrition represents a promising frontier in the fight against obesity.

Table 1.

Dietary pattern based on fat mass and obesity-associated (FTO) variants

Table 1. Long description

This table summarises multiple studies examining associations between FTO genetic variants and dietary patterns. Variants include rs9939609, rs1558902, rs3751812, rs8050136, and rs8044769. Study designs include cross-sectional, observational, randomized controlled trials, and systematic reviews, with populations ranging from children to adults across diverse ethnic groups.

Reduced intake of discretionary foods for individuals with the FTO rs9939609 genotype

Recent research on gene–environment interactions has highlighted how dietary intake influences the relationship between genetic markers and metabolic health, body composition, and fat accumulation.

A cross-sectional analysis of baseline data from the Food4Me study, a six-month randomised controlled trial conducted across seven European countries, examined the association between the FTO rs9939609 genotype, dietary intake, and adiposity-related outcomes in approximately 1,280 adults, focusing on discretionary foods – energy-dense, nutrient-poor items like sugary snacks and fast food. The study found that a dietary pattern high in discretionary foods was linked to higher BMI and larger waist circumference (WC). In parallel, the FTO rs9939609 risk genotype was associated with higher BMI and waist circumference; however, no evidence of a dietary interaction with the genotype was observed^{(Reference Livingstone, Brayner and Celis-Morales26)}. The large multicountry sample and standardised methodology strengthen the reliability of these observations, although the cross-sectional design and reliance on self-reported dietary data limit causal inference. This may be due to limited power to detect interaction effects, reliance on self-reported dietary intake, and the observational nature of the analysis. Future research using longitudinal or intervention designs with improved dietary exposure assessment and larger genotype-stratified samples could be used to clarify the interaction further. Overall, this evidence reinforces population-wide recommendations to limit discretionary foods that are high in saturated fat and low in fibre. For individuals carrying the FTO rs9939609 genotype, who already exhibit higher BMI and WC, adherence to a dietary pattern that is low in discretionary foods and rich in fibre could be important for supporting healthy weight maintenance.

Further mechanistic evidence comes from paediatric research, where children and adolescents carrying one or two FTO rs9939609 A alleles (AA/AT) exhibited greater BMI, fat mass, and loss-of-control (LOC) eating episodes compared with TT subjects. In a buffet-style test meal, AA/AT youth consumed a higher proportion of energy from fat, suggesting that both LOC eating and preferential selection of energy-dense, palatable foods may mediate the effect of FTO on excess body weight^{(Reference Tanofsky-Kraff, Han and Anandalingam30)}. These findings highlight potential behavioural mechanisms underlying gene–diet interactions and suggest that early dietary interventions targeting discretionary and high-fat foods may be particularly important for at-risk youth. In contrast, Sonestedt et al. explored how dietary fat intake interacts with the FTO rs9939609 genotype and found that individuals with the risk allele are more likely to gain weight when consuming high-energy diets, highlighting the importance of dietary control^{(Reference Sonestedt, Roos and Gullberg31)}. This observational cohort study used a modified diet history method to assess habitual dietary intake, incorporated direct anthropometric measurements, and collected detailed information on leisure-time physical activity, strengthening exposure and outcome assessment compared with studies relying solely on self-reporting. Significant interactions were observed between FTO genotype and energy-adjusted fat intake (P = 0.04), as well as carbohydrate intake (P = 0.001), in relation to BMI. Notably, the increase in BMI across FTO genotypes was confined to individuals consuming high-fat diets. However, the observational design, reliance on self-reported dietary data, and predominantly European study population may introduce residual confounding and limit generalisability. Future studies could improve the detection of gene–diet interactions by using prospective or intervention designs, larger genotype-stratified samples, more objective dietary assessments, and greater ethnic diversity to better clarify how dietary patterns influence obesity risk according to genetic background.

Adding to this evidence, a recent cross-sectional study in an urban Argentinian population (n = 173) found that A-carriers of rs9939609 consumed more total fat, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and fat-rich ultraprocessed foods, while consuming slightly less carbohydrate than TT homozygotes. A-carriers also adhered more to a Western dietary pattern and consumed more ‘milk and yogurt’ and ‘animal fats’^{(Reference Olmedo, Luna and Zubrzycki32)}. These findings confirm that the FTO rs9939609 A allele contributes to nutrient and food intake variability across populations, particularly increasing the consumption of SFA-enriched foods. From a public health perspective, this highlights that A-carriers may be less adherent to dietary guidelines limiting saturated fat intake, reinforcing the relevance of tailored dietary advice in precision nutrition approaches.

High-level evidence from a systematic review and meta-analysis by Livingstone et al. indicates that individuals with the FTO risk allele (rs9939609) show increased energy intake, especially from high-calorie, low-nutrient foods, and observes how reducing discretionary foods could help manage obesity risk. Despite higher energy intake observed among risk allele carriers, carriage of the FTO rs9939609 minor allele does not impair response to dietary, physical activity, or drug-based weight loss interventions^{(Reference Livingstone, Celis-Morales and Papandonatos33)}. This suggests that lifestyle interventions remain effective for individuals with genetic susceptibility. Future research could explore whether personalised dietary strategies, such as targeted reduction of discretionary foods, further enhance intervention efficacy across different populations or ethnic groups.

FTO rs9939609 and reduced response to diet and lifestyle interventions

Recent advances in research on gene–environment interactions have deepened our understanding of how dietary intake influences the relationship between genetic markers and metabolic health, body composition, and fat mass accumulation. Individuals carrying the risk allele (A) of FTO rs9939609 tend to have a higher BMI and are at greater risk of obesity. Research shows that, despite engaging in dietary changes and physical activity, individuals with the FTO rs9939609 variant may experience less significant weight loss compared to non-carriers. This diminished response is believed to result from the FTO gene’s influence on appetite regulation and energy intake. Individuals with the risk allele have been shown to have a stronger preference for high-calorie foods and may exhibit less satiety after meals, leading to increased energy consumption. Although lifestyle interventions, such as calorie restriction and increased physical activity, are effective in managing weight, carriers of the FTO rs9939609 variant may need more tailored and intensive strategies to achieve comparable weight loss results. Moreover, some studies suggest that, while the short-term response to interventions might be limited, long-term adherence to a healthy diet and regular physical activity can still benefit individuals with the FTO risk allele.

A nutrigenetic intervention study in 18 adults who are either overweight or with obesity examined multiple genetic variants, including FTO rs9939609, in the context of adherence to a Mediterranean diet (Med-diet) and physical activity. Individuals carrying the A allele of FTO rs9939609 exhibited smaller reductions in weight and BMI and differential changes in PREDIMED scores (a measure of Med-diet adherence) compared with TT homozygotes, suggesting a potential interaction between genotype and dietary adherence^{(Reference Franzago, Di Nicola and Fraticelli34)}. While the intervention design allowed careful monitoring of diet, the small sample size and possible metabolic confounders (e.g., type 2 diabetes, impaired glucose regulation) limit statistical power and generalisability. Additionally, unassessed factors such as gut microbiota and epigenetic modifications may influence responses. In a longitudinal study of 193 adults with obesity, participants completed a 12-week formula-based weight loss programme followed by a 40-week weight maintenance phase. Homozygous A allele carriers (AA) of FTO rs9939609 had higher baseline BMI and body weight than TT homozygotes. Although initial weight loss was similar across genotypes, AA carriers of FTO rs9939609 showed less additional weight loss and greater weight regain during maintenance, highlighting a potential role of FTO in long-term weight stabilisation^{(Reference Woehning, Schultz and Roeder35)}.

Evidence from meta-analysis and controlled trials provides additional context. A meta-analysis of ten studies (comprising 6,951 participants) found that individuals carrying the FTO rs9939609 homozygous A allele may experience slightly greater weight loss than non-carriers in some settings, particularly in diet-only interventions and after adjusting for baseline BMI. However, effect sizes were generally small, and heterogeneity across studies limited the certainty of subgroup analyses^{(Reference Xiang, Wu and Pan36)}. Similarly, the two-year CALERIE phase 2 trial demonstrated that in healthy adults who are normal weight, the FTO rs9939609 genotype did not significantly influence adherence to prolonged caloric restriction or most body composition and biomarker outcomes, though minor genotype-specific differences in resting metabolic rate were observed^{(Reference Dorling, Belsky and Racette37)}. Together, these studies highlight that the influence of FTO rs9939609 on intervention response is modest, context-dependent, and not uniformly observed across study designs, revealing the need for larger, controlled, and diverse cohorts.

Mechanistic studies provide biological plausibility for these findings. Controlled trials have shown that rs9939609 A allele carriers exhibit attenuated postprandial suppression of acylated ghrelin, an orexigenic hormone, alongside altered neural responses to food cues in brain regions related to homeostatic and reward signalling. These hormonal and neural differences may promote increased energy intake and reduced satiety, partially explaining why standard interventions may be less effective in carriers^{(Reference Karra, Daly and Choudhury22,Reference Dorling, Clayton and Jones23)} . Importantly, these studies are mostly conducted in adults who are normal weight under controlled conditions, and further work is needed to confirm whether these physiological differences translate to real-world dietary behaviours and weight outcomes across diverse populations.

FTO rs9939609 and response to the Mediterranean diet

Variants of the FTO gene, particularly FTO rs9939609, have been consistently associated with increased obesity risk, largely mediated through effects on appetite regulation and energy intake. Given the anti-inflammatory and nutrient-dense characteristics of the Mediterranean diet, several studies have investigated whether adherence to this dietary pattern can modify the association between FTO rs9939609 and adiposity-related outcomes.

Evidence from large observational cohorts suggests that adherence to the Med-diet may attenuate the relationship between FTO risk alleles and measures of adiposity. In the PREDIMED trial, involving over 7,000 older adults at high cardiovascular risk, lifestyle factors including Med-diet adherence and physical activity were shown to modify associations between FTO rs9939609 and body weight outcomes. Participants with higher adherence to the Med-diet exhibited a reduced expression of genetic susceptibility to obesity, regardless of genotype^{(Reference Corella, Ortega-Azorín and Sorlí38)}. Strengths of this study include its large sample size and validated dietary assessment tools; however, reliance on self-reported intake, the older age of participants, and the high baseline cardiometabolic risk limit generalisability to younger and more diverse populations.

Supporting evidence from related PREDIMED analyses and other Mediterranean cohorts indicates that greater adherence to the Med-diet is associated with lower BMI and waist circumference among FTO rs9939609 risk allele carriers^{(Reference Martínez-González, Salas-Salvadó and Estruch39)}. Nevertheless, these findings are predominantly observational and do not establish causality. Furthermore, genotype–diet interactions were generally modest, suggesting that the Med-diet does not eliminate genetic risk but may partially offset it through favourable effects on satiety, energy density, and metabolic health.

Intervention evidence specifically testing genotype-stratified responses to the Med-diet remains limited. Small nutrigenetic trials have reported differential adherence or weight outcomes by FTO genotype; however, these studies are constrained by short duration, limited statistical power, and potential confounding from unmeasured factors such as gut microbiota or baseline metabolic status. Meta-analyses of dietary interventions more broadly indicate that lifestyle modification is effective across genotypes, with no consistent evidence that FTO rs9939609 carriers derive uniquely greater or lesser benefit from Med-diets.

Collectively, current evidence suggests that adherence to the Med-diet is associated with favourable weight and metabolic outcomes irrespective of FTO rs9939609 genotype, with possible modest attenuation of genetic risk among carriers. Rather than supporting genotype-specific dietary prescriptions, these findings reinforce the Med-diet as a broadly beneficial dietary pattern that may be particularly relevant for individuals with elevated genetic susceptibility to obesity. Further well-powered randomised controlled trials in diverse populations are required to clarify whether genotype-informed dietary guidance provides clinically meaningful advantages over standard evidence-based recommendations.

FTO rs9939609 and artificially sweetened beverages

Artificially sweetened beverages (ASBs) have been the subject of debate regarding their role in weight management. Individuals carrying FTO rs9939609 were linked to increased appetite, energy intake, and a higher risk of obesity. Studies suggest that individuals with these genetic variants may have different responses to ASBs compared to the general population. Similarly, individuals with the risk variant, known for its role in regulating hunger and energy balance, may experience compensatory overeating when consuming ASBs due to incomplete satiety signalling. Research has found that, despite their low caloric content, ASBs may not effectively reduce overall energy intake or body weight in carriers of these risk alleles, potentially leading to weight gain or limited effectiveness in weight loss strategies. While the exact mechanisms remain unclear, the interaction between ASBs and the FTO rs9939609 variant suggests that ASBs may not be a beneficial tool for weight management in individuals carrying the rs9939609 obesity risk allele.

A Norwegian study by Bjørnland et al. investigated the modifying effects of age, sex, and lifestyle factors on the association between the FTO rs9939609 variant and obesity in 25,686 participants. The genetic association with BMI was stronger in younger compared with older individuals, and more pronounced among physically inactive participants. Sex-specific differences were observed in relation to ASB intake. Although BMI increased with increasing intake of ASBs in both men and women, a significant gene–environment interaction between FTO rs9939609 and artificially sweetened beverage consumption was observed only in men. Among men with high intake, carriers of the FTO risk allele exhibited a higher BMI compared with non-carriers, whereas no genotype-related differences were evident among men with low intake. In women, no significant interaction was detected, with BMI increasing at a similar rate across FTO genotypes. The impact of FTO can differ between both age and gender^{(Reference Bjørnland, Langaas and Grill40)}. Many studies of FTO rs9939609 across diverse ethnic groups have included mixed-gender populations^{(Reference Livingstone, Brayner and Celis-Morales26,Reference Tanofsky-Kraff, Han and Anandalingam30–Reference Livingstone, Celis-Morales and Papandonatos33)} . This indicates the importance of analysing gender separately, as observed differences could reflect true biological variation, gender-specific responses, age-related effects, or differences in dietary and lifestyle habits. Understanding these variations could be important for developing personalised strategies for obesity prevention and management.

While ASBs are often promoted as a healthier alternative to sugar-sweetened beverages, their effectiveness may be limited in individuals with the FTO rs9939609 variant due to altered appetite regulation and compensatory eating behaviours. Therefore, generic dietary recommendations, such as replacing sugar-sweetened beverages with ASBs, may not be effective for everyone and could even be counterproductive for those with specific genetic variants. Future studies could be done to confirm this association.

FTO rs1558902 and high protein diet

The FTO rs1558902 variant, similar to other FTO gene polymorphisms, has been associated with increased BMI and a predisposition to obesity. Research indicates that dietary composition, particularly a high-protein diet, may mitigate some of the negative effects of this variant. High-protein diets are known to enhance satiety, preserve lean muscle mass, and promote fat loss, which can be especially beneficial for individuals with genetic susceptibility to weight gain, such as those carrying the FTO rs1558902 risk allele. Several studies suggest that individuals with the FTO rs1558902 variant may experience better weight loss outcomes and improvements in body composition when following a high-protein diet compared to other macronutrient compositions. This enhanced response is probably due to the protein’s ability to suppress appetite and reduce overall energy intake, helping to offset the increased hunger and food preference for energy-dense foods commonly observed in individuals with FTO variants. While the FTO rs1558902 variant has been linked to higher risk of obesity, adopting a high-protein diet may provide an effective dietary intervention for better weight management and appetite control.

Studies examining gene–diet interactions have shown that certain dietary factors, such as low fat intake, can modify the impact of the FTO gene on BMI or fat distribution. Stronger evidence comes from a randomised controlled trial, which investigated the potential influence of the FTO rs1558902 variant on weight loss in a two-year dietary intervention study involving 742 adults with obesity of mixed gender, predominantly of European ancestry. Findings indicated that individuals carrying the risk allele of the FTO variant experienced greater reductions in weight when following a high-protein diet. Conversely, a contrasting genetic effect was observed regarding changes in fat distribution in response to a low-protein diet. This study suggests that a high-protein diet may be beneficial for weight loss for individuals with the risk allele of the FTO variant rs1558902. The long follow-up duration of controlled dietary intervention and adjustment for key confounders strengthen the internal validity of these findings. However, the limited ethnic diversity of the cohort restricts extrapolation to non-European populations, and changes in body composition beyond body weight were not comprehensively assessed^{(Reference Zhang, Qi and Zhang41)}.

In contrast, cross-sectional observational studies can show associations, but they cannot prove cause and effect. A study of 1,491 young adults (20–29 years) from mixed ethnic backgrounds reported that East Asian individuals homozygous for the rs1558902 risk allele exhibited significantly higher BMI and WC under conditions of low protein intake (≤18% of total energy). In contrast, no statistically significant genotype-related differences in BMI or waist circumference were observed among individuals consuming higher-protein diets (>18% of total energy), consistent with a significant FTO–protein interaction (BMI: P= 0.01; WC: P = 0.007). Although the overall sample size and ethnic stratification strengthen the exploratory value of the analysis, the number of risk allele homozygotes was small, particularly among East Asians, limiting statistical power. Dietary intake was assessed using a food frequency questionnaire, which is subject to recall bias and measurement error^{(Reference Merritt, Jamnik and El-Sohemy42)}. Taken together, evidence from randomised controlled trials and observational studies suggests that higher dietary protein intake may partially offset the obesogenic effects of the FTO rs1558902 variant, although the strength and generalisability of this interaction vary by study design and population.

Dietary macronutrient distribution and fibre intake in carriers of FTO rs3751812 and FTO rs8050136

Evidence from observational studies suggests that macronutrient composition and dietary fibre intake may modify the association between certain FTO variants and adiposity-related outcomes. A study conducted by Czajkowski et al., in a Polish Caucasian population, demonstrates that carriers of the GG genotype of FTO rs3751812 and the CC genotype of FTO rs8050136 exhibit lower body weight, BMI, and total body fat when their habitual energy intake included more than 48% of carbohydrates and less than 30% fat^{(Reference Czajkowski, Adamska-Patruno and Bauer43)}. While these findings are consistent with dietary reference ranges for carbohydrates and fat intake^{(Reference Ryan-Harshman and Aldoori44)}, the cross-sectional design limits causal inference, and dietary intake was assessed using self-reported methods, which are prone to recall bias and measurement error. Additionally, Hosseini-Esfahani et al. reported that fibre intake influenced the association between multiple FTO variants, including FTO rs3751812, FTO rs8050136, FTO rs1421085, FTO rs1121980, FTO rs17817449, and FTO rs9939973 and obesity risk, with stronger effects observed among individuals consuming higher levels of dietary fibre and carrying multiple risk alleles^{(Reference Hosseini-Esfahani, Koochakpoor and Daneshpour45)}. Consistent with this, another study found that daily fibre intake above 18 g was associated with lower hip circumference in GG carriers of FTO rs3751812 and CC carriers of FTO rs8050136^{(Reference Czajkowski, Adamska-Patruno and Bauer46)}. Although these findings support a potential protective role of dietary fibre, the reliance on anthropometric proxies and observational designs precludes conclusions regarding causality or long-term effects.

However, the evidence base is largely observational, geographically limited, and heterogeneous with respect to dietary assessment methods and outcome measures. Multiple testing across SNPs also raises the possibility of chance findings. Despite these limitations, available data suggest that macronutrient composition and dietary fibre intake may modify obesity risk in carriers of FTO variants, supporting the conceptual promise of precision nutrition. Nonetheless, causality cannot yet be established. Confirmation in well-designed randomised controlled trials and in ethnically diverse populations is required.

Macronutrient intake patterns (carbohydrate and protein distribution) in relation to FTO rs8044769

Panoutsopoulou et al. have examined the role of the FTO rs8044769 in knee and hip osteoarthritis (OA) risk, considering BMI. Data from UK and Australian cohorts (5,409 knee OA cases, 4,355 hip OA cases, and up to 5,362 controls) showed that the FTO rs8044769 variant was significantly associated with overweight (BMI ≥ 25) and knee OA^{(Reference Panoutsopoulou, Metrustry and Doherty47)}. Evidence for FTO rs8044769 remains inconsistent across populations, and some have reported no association. Dai et al. examined the association between the FTO rs8044769 and its potential link to BMI and OA in a Chinese Han population. A case-control approach was used with 890 OA cases and 844 controls, but no significant association was found between rs8044769 and BMI or OA susceptibility^{(Reference Dai, Ying and Shi48)}. However, in African Americans, T allele carriers of FTO rs8044769, when present in heterozygous form, may protect against higher BMI levels, but only in early adulthood (20s and 30s)^{(Reference Nock, Plummer and Thompson49)}. These variants and their effect on BMI may vary by ethnicity and other factors, as different ethnic groups have distinct dietary practices. Given the limited studies on FTO rs8044769 and the mixed findings across populations, future research should focus more on diverse ethnic groups to better understand how these variants influence BMI and to develop personalised dietary recommendations for more effective obesity management.

Czajkowski et al. found that in Caucasian subjects of Polish origin, body weight and BMI were significantly higher in TT and CT carriers of FTO rs8044769 if daily energy intake derived from carbohydrates was less than 48%. Moreover, TT carriers of FTO rs8044769 observed higher blood glucose concentration while fasting if more than 18% of total energy intake was derived from proteins^{(Reference Czajkowski, Adamska-Patruno and Bauer43)}. However, given the limited number of studies, mixed results across ethnic groups, and the observational nature of the evidence, these findings should be interpreted cautiously. Further studies in diverse populations are needed before translating these gene–macronutrient interactions into precise personalised dietary recommendations.

Table 2 outlines details of studies on the FTO gene and its association with obesity.

Table 2.

Details of studies on the FTO genes associated with obesity used in the literature search

Table 2. Long description

This table summarises studies included in the literature search examining associations between FTO gene variants and obesity-related traits. It presents each study’s FTO variant(s), study details and results.

Limitations and challenges of nutrigenetics and precision nutrition in obesity

While nutrigenetics and precision nutrition show great potential in preventing and managing obesity, some challenges and limitations hinder their implementation in biomedical research and clinical practice. One major limitation is the control of participants’ dietary intake; however, the use of specific biomarkers for food intake could potentially overcome this obstacle^{(Reference Marcum50)}.

High-energy and ultraprocessed foods high in sodium, added sugars, and saturated fats are readily available in stores and restaurants, making them common in households. These environments, especially in lower socioeconomic neighbourhoods, create obstacles such as limited access to fresh and healthy products and an abundance of fast-food options. Additionally, high-energy and ultraprocessed foods are often cheaper than healthier alternatives, leading to economic constraints that favour the consumption of less nutritious options. Social, cultural, economic, and political factors, including advertising and large portion sizes, further complicate efforts to promote healthy eating^{(Reference Chatelan, Bochud and Frohlich51)}.

Public acceptance and ethical concerns also pose significant barriers. A population-based study from Quebec, Canada reported generally positive attitudes toward nutrigenetic testing and its potential benefits. However, participants expressed concerns regarding data privacy, ownership of genetic information, and confidentiality. Cost was identified as a major barrier, with willingness to pay strongly associated with higher socioeconomic status, suggesting that precision nutrition approaches may exacerbate existing health inequalities if access remains limited^{(Reference Vallée Marcotte, Cormier and Garneau52)}.

Regulatory oversight remains another challenge. Although the US Food and Drug Administration approved direct-to-consumer genetic testing by 23andMe in 2017, these tests have limited clinical sensitivity. Moreover, many unregulated companies now offer nutrigenetic-based dietary advice with variable scientific validity. A survey of online DNA testing services revealed that most provided health- and nutrition-related recommendations, raising concerns about accuracy, standardisation, and the potential for misleading health claims^{(Reference Moore53)}.

AǦagündüz & Gezmen-KaradaǦ investigated the relationship between the FTO gene (rs9939609) polymorphism and body fat markers in 200 Turkish adults (18–65 years old). Results showed that individuals with the AA genotype had significantly higher total body fat percentages compared to those with AT and TT genotypes, especially in females. However, no significant differences were found in abdominal fat levels, BMI, body adiposity index (BAI), and lipid accumulation products (LAP) across genotypes^{(Reference AǦagündüz and Gezmen-KaradaǦ54)}. According to the study, the FTO rs9939609 variant influences overall body fat accumulation but not abdominal fat in Turkish adults. A similar cross-sectional study was done by Mohammed et al., which examined the association between the FTO rs9939609 and the risk of obesity and type 2 diabetes (T2D) in 201 healthy young university students in Kuwait, and found no significant association between FTO variants and BMI or the risk of T2D. The study concludes that FTO is not a significant predictor of obesity or T2D in young Kuwaiti adults^{(Reference Jamali, Abdeen and Mathew55)}. Even though meta-analyses and genome-wide association studies have identified FTO as a significant contributor to obesity, findings from those cross-sectional studies highlight inconsistencies in specific populations. These discrepancies may be due to small sample sizes, which limit statistical power and the ability to detect significant associations, and their impact may vary across different ethnicities, lifestyles, and environmental factors. To improve the predictive strength of such studies, future research in this field should be conducted on a broader scale with larger, more diverse populations to better understand the FTO polymorphisms in obesity.

Importantly, evidence that genotype-based advice improves behaviour is limited. A randomised study in young adults found that FTO-based personalised dietary and physical activity advice did not significantly improve healthy eating motivation compared with non-genotype-based advice or controls^{(Reference King, Glaister and Lawrence56)}. This suggests that the genetic component alone may not be enough to influence behaviour or motivate young adults to change their dietary habits. However, the study did not track actual changes in eating or physical activity behaviours, only self-reported motivation, so it is unclear whether genotype-based advice influenced real-life dietary or activity changes. The study followed participants for only a short period (one week after receiving advice), which might not be enough time for significant behaviour changes. Long-term follow-up would be necessary to assess the sustained impact of personalised advice. There is often a gap in understanding complex genetic data, so simplifying explanations and using relatable language is key. Public health messages could focus on how genetics interacts with lifestyle and environment rather than providing overly technical information. Developing apps or websites where individuals can input basic health data (age, weight, activity levels, and genetic information) to receive personalised nutrition tips might be a fun and accessible way to engage people.

High costs of genetic testing and limited access to nutrigenetic services can restrict widespread implementation, especially in lower-income populations. Regulatory oversight is currently limited, raising concerns about the accuracy, standardisation, and clinical validity of commercially available tests. Privacy, data security, and the potential for genetic discrimination are key ethical issues that must be addressed. Furthermore, there is a risk of overemphasising genetic determinism, which may lead individuals to overlook the important role of lifestyle and environmental factors. Clear communication and education are essential to ensure that personalised nutrition recommendations are evidence-based, practical, and ethically responsible.

Future directions in nutrigenetics and precision nutrition for obesity

The application of genetic and molecular pathway information for understanding nutrient utilisation and metabolism is crucial for personalised nutrition. This knowledge is made possible by the advancements in ‘omics’ technologies. Future research should aim to integrate data from genomics, epigenomics, transcriptomics, proteomics, and metabolomics to gain a comprehensive understanding of how individuals respond to different diets. By adopting this approach, more precise and actionable insights can be uncovered^{(Reference Ferguson, De Caterina and Görman57)}. By leveraging advanced technologies, genetic and environmental factors can be integrated more effectively and accurately. This includes utilising methods like GWAS, genetic risk score (GRS) calculations, and machine learning models such as support vector machines and random forest algorithms. These technologies enable the analysis of large datasets and the identification of complex patterns, leading to more precise predictions. The application of these technologies and strategies in precision nutrition holds great promise for weight loss. They have the potential to accurately predict individual responses to different weight loss regimens and facilitate personalised dietary interventions^{(Reference Chen and Chen58)}. Precision nutrition encompasses big data management and ethical analysis. It involves incorporating genetic information, as well as phenotypic, cultural, behavioural, and lifestyle preferences, to maintain health and manage diseases. This approach guides both general and personalised counselling. Health information and communication technology, coupled with artificial intelligence (AI), can play a role in controlling and promoting nutritional health among diverse population groups^{(Reference Baena de Moraes Lopes, Ferreira and Honório Ferreira59)}. The promising use of AI necessitates the fast and dependable analysis of numerous variables gathered during monitoring. Artificial neural networks (ANNs) are crucial tools for achieving precision in AI, especially in precision applications. Nutrigenetic counselling provides personalised dietary advice based on an individual’s genetic information. The accurate prediction of resting energy expenditure (REE) through ANNs enhances the information available for such counselling sessions, enabling more targeted and effective dietary recommendations^{(Reference Baena de Moraes Lopes, Ferreira and Honório Ferreira59,Reference Disse, Ledoux and Bétry60)} .

Uncertainties of current predictions associated with nutrigenetics and how it affects the outcome

Nutrigenetics and personalised nutrition together represent a promising complementary approach. Nevertheless, uncertainties exist. Human genetics is highly complex, and the interactions between multiple genes and nutrients are not fully understood.

The complexity involved makes it challenging to foresee the effects of particular genetic variations on nutrient metabolism and health outcomes^{(Reference Zhang, Qi and Zhang41)}. Small effect sizes of individual genetic variants, such as those in the FTO gene, mean that very large sample sizes are required to reliably detect gene–diet or gene–lifestyle interactions. Many nutrigenetic studies have limited participant numbers, which reduces statistical power, increases the likelihood of false-positive findings, and limits reproducibility. Furthermore, predictions made by nutrigenetics often do not fully account for environmental and lifestyle factors, such as physical activity, stress, or overall diet, which can significantly influence health outcomes. As a result, dietary recommendations based on these studies may be incomplete or inaccurate. Until larger, well-powered, and diverse cohorts are studied, the clinical utility of many nutrigenetic findings remains uncertain^{(Reference Rajesh, Varanavasiappan and Ramesh61)}. Many nutrigenetic claims are still based on emerging evidence. The findings of numerous studies may not always be reproducible due to their small sample sizes. The lack of robust evidence can result in uncertainty surrounding the recommendations given^{(Reference Cole and Gabbianelli62)}.

The issue of privacy, data security, and the possibility of genetic discrimination raises ethical concerns^{(Reference Marcum50)}. Moreover, there is a potential for generating unrealistic expectations among consumers regarding the advantages of personalised nutrition^{(Reference Grimaldi, van Ommen and Ordovas63)}.

These uncertainties can affect the outcomes of nutrigenetic predictions by leading to inconsistent or inaccurate dietary recommendations, which may not effectively improve health or could even cause harm if not properly validated.