Introduction: Childhood obesity continues to pose a significant global public health concern, with its rising prevalence attributed to both environmental exposures and genetic predispositions. Among the primary genetic determinants are the fat mass and obesity-associated gene (FTO) and the leptin gene (LEP), which are integral to the regulation of appetite, satiety, and overall energy homeostasis.Variants within these genes have been implicated in promoting altered eating behaviors, heightened caloric intake, and an increased propensity for weight gain in children. This systematic review seeks to consolidate current evidence regarding the impact of FTO and LEP polymorphisms on pediatric nutritional status.Method: A systematic literature search was conducted on 29 April 2025 using PubMed, EMBASE, and Scopus databases. Keywords included “FTO,” “LEP,” “gene variant,” “childhood nutrition,” “obesity,” and “methylation.” Eligible studies were original human research involving individuals aged 0–18 years, examining associations between FTO and/or LEP gene variants and nutritional outcomes such as body mass index (BMI), dietary behavior, or relevant metabolic biomarkers.Studies investigating epigenetic mechanisms, such as DNA methylation of these genes in relation to nutrition, were also included. Article screening and data extraction were performed independently by two reviewers. The Newcastle–Ottawa Scale (NOS) was applied to assess the methodological quality and risk of bias in cohort and case-control studies.Results: Nine studies synthesizing 22,350 participants were eligible for analysis. Consistently, the FTO variant, rs9939609 A allele, had an association with increased BMI (p < 0.01), fat mass (p = 0.01), and energy intake (p = 0.006). AA and AT genotype associations were noted for obesity risk ranging from 1.2 to 5.89 fold increase. One study reported an odds ratio of 4.24 for obesity in a cohort of boys. Additionally, this allele was associated with lower responsiveness to satiation (p = 0.008), higher triglyceride levels, and elevated free leptin index.Resting energy expenditure demonstrated an increase (p = 0.03), although it was still statistically within the suggested range. The intron 3 FTO variant rs8061518 had associations with lower risk of obesity and lower leptin levels, suggesting a protective role. Another FTO variant, rs99305069, was found in combination with LPL Ser447Ter genotype to have reduced risk of obesity. Two studies focusing on the LEP rs7799039 variant did not find any noteworthy relationships to BMI or obesity, but one study did suggest a link to lower levels of adiponectin and lung function impairment.Conclusion: Changes in the FTO gene, particularly the variant rs9936969, are associated with increased risk of childhood obesity due to changes in appetite drive and leptin signaling pathways. The contributing role of the polymorphism rs8061518 strengthens the argument of diverse functional impacts of FTO polymorphisms. Despite the absence of evidence suggesting a significant link between LEP rs7799039 and the risk of obesity in children, the scant available literature restricts drawing firm conclusions.
