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

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-07-10 DOI:10.1111/cns.70510

Pei Xiao, Yan Li, Jiayuan Dai, Jingfan Xiong, Jie Mi

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Abstract

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.

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肥胖症影响脑功能网络的关键生命阶段的鉴定

观察性研究表明，肥胖影响大脑功能连接，但这些影响的关键发育时期尚不清楚。在此，我们旨在探讨生命过程体重与脑功能连通性之间的因果关系。方法采用孟德尔随机化（MR）方法推断生命历程体重(出生体重[n = 80,745]，儿童体重指数[BMI；n = 39,620]，成年期BMI [n = 322,154])和191个静息状态功能磁共振成像特征（n = 34,691），使用全基因组关联数据。通过联动不平衡评分回归和共定位分析来强化因果关系。通过两步介导MR、转录组全关联研究和富集分析来探索潜在的机制。结果成年期BMI增加了额叶神经活动（β = 0.078, 95% CI: 0.029 ~ 0.127），而儿童期BMI降低了皮质下小脑与运动或注意网络之间的功能连通性（β = - 0.087, 95% CI: - 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通性（β = - 0.147, 95% CI: - 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鉴定出neurexophilin-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% CI: 2.6%-52.0%, p = 0.048）。此外，转录分析揭示了不同生命阶段体重和脑功能连接之间的优先基因和途径。结论：该研究表明，体重对大脑功能网络有明显的生命阶段特异性影响，强调需要在整个生命过程中进行有针对性的干预，以减轻早期肥胖对大脑健康的持续影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.