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Herein, we aimed to investigate the causal relationships between life\u2010course body weight and brain functional connectivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Mendelian randomization (MR) was applied to infer the causality between life\u2010course body weight (birth weight [<jats:italic>n<\/jats:italic>\u2009=\u200980,745], childhood body mass index [BMI; <jats:italic>n<\/jats:italic>\u2009=\u200939,620], and adulthood BMI [<jats:italic>n<\/jats:italic>\u2009=\u2009322,154]) and 191 resting\u2010state functional magnetic resonance imaging traits (<jats:italic>n<\/jats:italic>\u2009=\u200934,691) using genome\u2010wide association data. Linkage disequilibrium score regression and colocalization analysis were conducted to reinforce the causality. Two\u2010step mediation MR, transcriptome\u2010wide association studies, and enrichment analyses were performed to explore the underlying mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Adulthood BMI increased neural activity in the frontal lobe (<jats:italic>\u03b2<\/jats:italic>\u2009=\u20090.078, 95% CI: 0.029\u2009~\u20090.127), whereas childhood BMI reduced functional connectivity between the subcortical\u2010cerebellum and motor or attention network (<jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.087, 95% CI: \u22120.144\u2009~\u2009\u22120.031). Birth weight decreased the functional connectivity of the central executive or default mode network in the temporal lobe (<jats:italic>\u03b2<\/jats:italic>\u2009=\u2009\u22120.147, 95% CI: \u22120.217\u2009~\u2009\u22120.078). These causalities were consistent with the MR sensitivity analyses and colocalization results. The mediation MR identified neurexophilin\u20103 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%\u201352.0%, <jats:italic>p<\/jats:italic>\u2009=\u20090.048). Furthermore, transcriptional analysis revealed prioritized genes and pathways that interconnect body weight at different life stages and brain functional connectivity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrated distinct life\u2010stage\u2010specific 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\u2010life obesity on brain health.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cns.70510","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T07:11:27Z","timestamp":1752131487000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of the Critical Life\u2010Stage of Obesity Contributing to Brain Functional Networks"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9976-7655","authenticated-orcid":false,"given":"Pei","family":"Xiao","sequence":"first","affiliation":[{"name":"Center for Non\u2010Communicable Disease Management, Beijing Children's Hospital, Capital Medical University National Center for Children's Health  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6780-1871","authenticated-orcid":false,"given":"Yan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Child and Adolescent Chronic Disease Prevention Shenzhen Center for Chronic Disease Control  Shenzhen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2948-8519","authenticated-orcid":false,"given":"Jiayuan","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Rare Diseases, State Key Laboratory of Complex Severe and Rare 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