Gene-exercise interaction on brain health in children with overweight/obesity: the ActiveBrains randomized controlled trial.

We investigated the interaction between a genetic score and an exercise intervention on brain health in children with overweight/obesity. One hundred one children with overweight/obesity (10.0 ± 1.5 yr, 59% girls) were randomized into a 20-wk combined exercise intervention or a control group. Several cognitive and academic outcomes were measured with validated tests. Hippocampal volume was quantified using magnetic resonance imaging. Six brain health-related polymorphisms [rs6265 (), rs2253206 (), rs2289656 (), rs4680 (), rs429358, and rs7412 ()] were genotyped. Cognitive flexibility and academic skills improved significantly more in the exercise than in the control group only in the children with a "favorable" genetic profile [mean -score, 0.41-0.67 (95% CI 0.11 to 1.18)], yet not in those with "less favorable" genetic profile. An individual response analysis showed that children responded to exercise in cognitive flexibility only in the "genetically favorable" group [i.e., 62% of them had a meaningful (≥0.2 Cohen ) increase in the exercise group compared with only 25% in the control group]. This finding was consistent in per-protocol and intention-to-treat analyses ( = 0.01 and = 0.03, respectively). The results were not significant or not consistent for the rest of outcomes studied. Our findings suggest that having a more favorable genetic profile makes children with overweight/obesity more responsive to exercise, particularly for cognitive flexibility. Interindividual differences have been reported in brain health-related outcomes in response to exercise interventions in adults, which could be partially explained by genetic background differences. However, the role of genetic polymorphisms on brain health-related outcomes in response to exercise interventions remains unexplored in pediatric population. The current study in children with overweight/obesity showed that a genetic score composed of six brain health-related polymorphisms (, , , , and ) regulated the exercise-induced response on several brain health outcomes, yet mainly and more consistently on cognitive flexibility.