Energy Intake-Dependent Genetic Associations with Obesity Risk: BDNF Val66Met Polymorphism and Interactions with Dietary Bioactive Compounds

Obesity represents a complex interplay between genetics, nutrition, and lifestyle. This study aimed to elucidate the intricate relationship between genetic variants, energy intake, and bioactive compounds in influencing obesity risk, particularly in low energy intake, to reveal how dietary intake modulates molecular-level interactions. We analyzed 53,117 participants stratified by obesity status and energy intake levels. Genome-wide association studies explored the genetic variants associated with obesity risk in low-energy- and high-energy-intake subgroups. Advanced computational approaches, including molecular docking, k-means clustering, and uniform manifold approximation and projection (UMAP), were employed to analyze interactions between missense variants and natural compounds. Ten genetic variants were significantly associated with obesity, particularly in participants with low energy intake. The most prominent variants included brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265). Molecular docking identified 152 bioactive compounds with strong binding affinity to BDNF Val66Met, including 107 compounds binding to both wild and mutant types. Citrus fruits and green vegetables showed selective binding to the mutant type. Antioxidant nutrient intake (anthocyanins, isoflavonoids, vitamins C and E, selenium) was higher in lean versus obese individuals in the high-energy-intake group. Alcohol consumption and selenium intake modulated polygenic risk scores’ influence on obesity risk in high-energy-intake individuals. Notably, citrus fruit intake correlated with lower BMI across all BDNF rs6265 genotypes. In conclusion, energy intake-specific genetic associations with obesity and identifies potential bioactive compounds for targeted interventions. The findings suggest that antioxidant nutrient intake, particularly from citrus fruits, may help manage obesity risk, especially in individuals with specific genetic variants.