Response of FTO gene polymorphisms to continuous caloric restriction diets on lipid and glycemic biomarkers in overweight and obese adults: a systematic review and meta-analysis

BACKGROUND: Common variants in the fat mass and obesity-associated (FTO) gene are linked to obesity and cardiometabolic risk, but whether they modify lipid and glycemic responses to continuous energy restriction (CER) remains unclear. We evaluated genotype-specific changes in lipid and glycemic biomarkers following CER-based dietary interventions in adults with overweight/obesity. METHODS: A literature search of four databases identified eligible intervention trials published through March 2026. Results were synthesized using random-effects meta-analyses, reporting mean differences (MDs) with 95% confidence intervals (CI). Subgroup analyses and sensitivity analyses were conducted, and the certainty of evidence was assessed. RESULTS: Fifteen articles (18 effect sizes for lipid outcomes; 21 for glycemic outcomes; 4,941 participants). Compared with non-carriers, FTO risk-allele carriers had higher triglycerides (MD 5.98 mg/dL; 95% CI 1.03 to 10.93). No significant genotype-related differences were observed for total cholesterol, LDL-C, HDL-C, fasting glucose, insulin, or HOMA-IR, and all sensitivity analyses were consistent with these findings. Subgroup tests showed no significant differences by intervention duration, study design or genotype model. Genotype-contrast analyses suggested differences in triglycerides and LDL-C (higher TG in AA carriers and greater LDL-C reduction in AA carriers) and in fasting glucose (greater reduction in AT/AA carriers) compared with non-carriers. Overall certainty of evidence ranged from low to very low (GRADE). CONCLUSIONS: Most lipid and glycemic markers were comparable across FTO genotypes during CER, whereas triglycerides were higher in risk-allele carriers. Replication in prospective trials with pre-specified genetic stratification is needed before these findings can inform clinical practice.