Al-Suhaimi Ebtesam Abdullah, AlRubaish Abdullah A, Aldossary Hanan A, Homeida Mohamed A, Shehzad Adeeb, Homeida Abdelgadir M
Vice presidency for Scientific Research and Innovation, Imam Abdulrahman Bin Faisal University (IAU), P.O. Box 1982, Dammam, 31441, Saudi Arabia.
King Abdulaziz and His Companions Foundation for Giftedness and Creativity "Mawhiba", Riyad, 11372, Saudi Arabia.
Mol Neurobiol. 2025 Aug 1. doi: 10.1007/s12035-025-05262-0.
The signal transduction and communication between adipose tissue-secreted adipokines and the central nervous system (CNS) are increasingly recognized for their role in metabolic and neurological regulation. This crosstalk contributes to the vulnerability of individuals with obesity to developing cognitive impairment. However, the detailed underlying molecular mechanisms through which obesity-induced peripheral changes influence blood-brain barrier (BBB) and CNS function remain under investigation. Among the key mediators of this interaction are signaling molecules (adipokines) secreted by white adipose tissue that regulate various physiological processes, including energy homeostasis, neural integrity, and immune responses. Obesity is associated with dysregulated leptin secretion due to adipose tissue dysfunction, contributing to metabolic abnormalities and hippocampal synaptic disturbances-factors that increase the risk of comorbid conditions, cognitive decline, and neurodegenerative disorders such as Alzheimer's disease. Additionally, obesity increases inflammatory molecules such as RAGE, LRP1, cytokines (IL-6 and TNF-α), leptin, insulin, and free fatty acids, which perturb amyloid-β degradation and promote accumulation in the brain while impairing brain-to-blood clearance. An electronic search was performed using Web of Science, Scopus, and PubMed to collect English-language articles published from 2010 to 2025 related to the role of leptin in obesity and neurodegenerative diseases. This study underpins recent literature on the mechanisms by which obesity-induced modulation of leptin signaling impacts cognitive decline, BBB dysfunction, and the pathogenesis of Alzheimer's disease. Thus, understanding leptin-driven mechanisms and developing targeted strategies, including leptin sensitization and BBB-protective interventions, could serve as effective therapeutic approaches to managing cognitive impairment associated with obesity.
脂肪组织分泌的脂肪因子与中枢神经系统（CNS）之间的信号转导和通讯在代谢和神经调节中的作用日益受到认可。这种相互作用导致肥胖个体易患认知障碍。然而，肥胖引起的外周变化影响血脑屏障（BBB）和中枢神经系统功能的详细潜在分子机制仍在研究中。这种相互作用的关键介质包括白色脂肪组织分泌的信号分子（脂肪因子），它们调节各种生理过程，包括能量稳态、神经完整性和免疫反应。由于脂肪组织功能障碍，肥胖与瘦素分泌失调有关，这会导致代谢异常和海马突触紊乱，这些因素会增加合并症、认知衰退和神经退行性疾病（如阿尔茨海默病）的风险。此外，肥胖会增加炎症分子，如RAGE、LRP1、细胞因子（IL-6和TNF-α）、瘦素、胰岛素和游离脂肪酸，这些分子会干扰淀粉样β蛋白的降解，促进其在大脑中的积累，同时损害脑-血清除。使用Web of Science、Scopus和PubMed进行电子检索，以收集2010年至2025年发表的与瘦素在肥胖和神经退行性疾病中的作用相关的英文文章。本研究为最近关于肥胖诱导的瘦素信号调节影响认知衰退、血脑屏障功能障碍和阿尔茨海默病发病机制的文献提供了支持。因此，了解瘦素驱动的机制并制定针对性策略，包括瘦素致敏和血脑屏障保护干预措施，可能是管理与肥胖相关的认知障碍的有效治疗方法。
