Identification of the Critical Life-Stage of Obesity Contributing to Brain Functional Networks.

AIMS: Observational studies suggest that obesity impacts brain functional connectivity, but critical developmental periods for these effects remain unclear. Herein, we aimed to investigate the causal relationships between life-course body weight and brain functional connectivity.

METHODS

Mendelian randomization (MR) was applied to infer the causality between life-course body weight (birth weight [n = 80,745], childhood body mass index [BMI; n = 39,620], and adulthood BMI [n = 322,154]) and 191 resting-state functional magnetic resonance imaging traits (n = 34,691) using genome-wide association data. Linkage disequilibrium score regression and colocalization analysis were conducted to reinforce the causality. Two-step mediation MR, transcriptome-wide association studies, and enrichment analyses were performed to explore the underlying mechanisms.

RESULTS

Adulthood BMI increased neural activity in the frontal lobe (β = 0.078, 95% CI: 0.029 ~ 0.127), whereas childhood BMI reduced functional connectivity between the subcortical-cerebellum and motor or attention network (β = -0.087, 95% CI: -0.144 ~ -0.031). Birth weight decreased the functional connectivity of the central executive or default mode network in the temporal lobe (β = -0.147, 95% CI: -0.217 ~ -0.078). These causalities were consistent with the MR sensitivity analyses and colocalization results. The mediation MR identified neurexophilin-3 as a potential mediator of the causal effect of birth weight on functional connectivity, explaining 27.3% of the total effect (95% CI: 2.6%-52.0%, p = 0.048). Furthermore, transcriptional analysis revealed prioritized genes and pathways that interconnect body weight at different life stages and brain functional connectivity.

CONCLUSION

This study demonstrated distinct life-stage-specific effects of body weight on brain functional networks, highlighting the need for targeted interventions across the life course to mitigate the persistent effect of early-life obesity on brain health.