Obesity Aggravates Status Epilepticus Through Lipocalin-2-mediated Inflammation and Necroptosis

Abstract

Obesity is an escalating global health concern associated with numerous comorbidities, including an elevated risk of neurodegenerative disorders. Status epilepticus, characterized by prolonged and recurrent seizures, leads to neuroinflammation and progressive neuronal cell death. Although obesity is recognized as a comorbidity in epilepsy, its mechanistic contribution to SE pathology remains poorly defined. This study investigated the effects of obesity on SE using leptin-deficient ob/ob mice, a well-established model of metabolic dysfunction. Pilocarpine was used to induce SE, and seizure progression was assessed. Compared to wild-type controls, ob/ob mice exhibited significantly reduced latency to seizure onset and a more rapid progression to SE. Fluoro-Jade B staining revealed markedly increased neuronal death in the CA1 and hilus regions of the hippocampus in ob/ob mice. Concurrently, immunofluorescence staining and western blot analysis showed robust astrocyte activation, evidenced by upregulated glial fibrillary acidic protein (GFAP). Obesity also intensified neuroinflammatory signaling, as evidenced by increased levels of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), along with increased expression of lipocalin-2 (LCN2) and phosphorylated signal transducer and activator of transcription 3(p-STAT3). Furthermore, necroptosis, a regulated form of cell death mediated by mixed lineage kinase domain-like protein (MLKL), was significantly enhanced in ob/ob mice following SE, as indicated by elevated phosphorylated MLKL (p-MLKL) expression. These results suggest that obesity exacerbated seizure susceptibility and amplifies neuroinflammatory and neurodegenerative processes in SE. This work highlights the LCN2-STAT3-MLKL signaling axis as a potential therapeutic target in obesity-associated seizure disorders and offers new insight into the interplay between systemic metabolism and epileptic brain injury.