Molecular mechanisms of blood-brain barrier dysfunction caused by obesity: pathophysiological understandings and treatment targets.

Chronic low-grade inflammation and systemic metabolic dysregulation are linked to obesity, a rapidly expanding worldwide health concern that affects the central nervous system (CNS) in addition to peripheral organs. Dysfunction of the blood-brain barrier (BBB), which impairs selective permeability, tight junction integrity, and neurovascular coupling, is one of its most serious neurobiological effects. The BBB, which is made up of pericytes, endothelial cells, and astrocytic end-feet, depends on specialized transporters and tight junction proteins like occludin, ZO-1, and claudin-5 to control the exchange of nutrients and xenobiotics. Pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and toll-like receptor 4 (TLR4) signaling cause obesity-induced meta-inflammation, which in turn causes endothelial NF-κB activation, leukocyte infiltration, and tight junction breakdown. BBB leakiness is simultaneously increased by intrinsic endothelial stress resulting from oxidative damage, mitochondrial dysfunction, defective autophagy, AMPK inhibition, and NAD⁺ depletion. LXR, PPAR, and ApoE signaling drive dysregulated lipid metabolism, which further impairs activity-dependent cerebral blood flow by interfering with neurovascular coupling and endothelial-astrocyte communication. By lowering inflammation, increasing tight junction expression, and boosting metabolic resilience, therapeutic interventions that target these molecular pathways, such as GLP-1 receptor agonists, PPAR-γ modulators, metformin, and statins, show promise in restoring the integrity of the BBB. Endothelial function is further reinforced, neuroinflammation is reduced, and BBB stability is supported by complementary lifestyle and dietary modifications such as regular exercise and nutrient-rich meals. The development of focused pharmaceutical and lifestyle approaches to prevent or correct neurovascular damage and concomitant cognitive decline is made possible by an understanding of the complex molecular pathways underlying obesity-related BBB dysfunction.