Obesity and Cognitive Function: Leptin Role Through Blood-Brain Barrier and Hippocampus

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.