Xiao Pei, Li Yan, Dai Jiayuan, Xiong Jingfan, Mi Jie
Center for Non-Communicable Disease Management, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Department of Child and Adolescent Chronic Disease Prevention, Shenzhen Center for Chronic Disease Control, Shenzhen, China.
CNS Neurosci Ther. 2025 Jul;31(7):e70510. doi: 10.1111/cns.70510.
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.
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.
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.
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.
观察性研究表明肥胖会影响大脑功能连接，但这些影响的关键发育时期仍不清楚。在此，我们旨在研究生命历程体重与大脑功能连接之间的因果关系。
应用孟德尔随机化（MR）方法，利用全基因组关联数据推断生命历程体重（出生体重[n = 80,745]、儿童期体重指数[BMI；n = 39,620]和成年期BMI[n = 322,154]）与191个静息态功能磁共振成像特征（n = 34,691）之间的因果关系。进行连锁不平衡评分回归和共定位分析以强化因果关系。进行两步中介MR、全转录组关联研究和富集分析以探索潜在机制。
成年期BMI增加了额叶的神经活动（β = 0.078，95%可信区间：0.029 ~ 0.127），而儿童期BMI降低了皮质下 - 小脑与运动或注意力网络之间的功能连接（β = -0.087，95%可信区间：-0.144 ~ -0.031）。出生体重降低了颞叶中央执行或默认模式网络的功能连接（β = -0.147，95%可信区间：-0.217 ~ -0.078）。这些因果关系与MR敏感性分析和共定位结果一致。中介MR确定神经外显蛋白 - 3是出生体重对功能连接因果效应的潜在中介，解释了总效应的27.3%（95%可信区间：2.6% - 52.0%，p = 0.048）。此外，转录分析揭示了在不同生命阶段连接体重与大脑功能连接的优先基因和途径。
本研究证明了体重在不同生命阶段对大脑功能网络有独特的影响，强调需要在生命历程中进行有针对性的干预，以减轻早年肥胖对大脑健康的持续影响。
