Ketogenic diet attenuates seizures by promoting lipid droplet formation via peroxisome proliferator-activated receptor gamma signaling pathway.

BACKGROUND: The ketogenic diet (KD) is an established therapy for drug-resistant epilepsy, yet its antiseizure mechanisms remain unclear. This study investigates whether KD modulates lipid metabolism-related genes to exert antiseizure effects in a mouse model of temporal lobe epilepsy. METHODS: Chronic epilepsy was induced in adult mice via systemic kainic acid (KA). Epileptic mice were fed either a standard chow diet (CD) or KD. Seizure activity was monitored via electroencephalography and behavioral scoring. Temporal lobe transcriptomic changes were analyzed using RNA sequencing. The role of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway was investigated in vivo and in primary hippocampal neurons using pharmacological agonists/antagonists and siRNA-mediated knockdown. RESULTS: KD-fed mice exhibited significantly reduced seizure frequency and severity compared to CD-fed controls. Transcriptomic analysis identified 41 differentially expressed lipid metabolism-related genes in the KD group. Perilipin 1 (Plin1) emerged as a top hub gene and was markedly upregulated in the hippocampus of KD-fed mice, associated with a significant increase in neuronal lipid droplet formation. In vitro, KD's effects were recapitulated by a PPARγ agonist and blocked by an antagonist, demonstrating that PPARγ mediates this transcriptional regulation. Knockdown of Plin1 in KA-treated neurons reduced lipid droplet formation and concurrently increased neuronal excitability (c-Fos expression), establishing a direct mechanistic link. CONCLUSION: The ketogenic diet exerts antiseizure effects that may be related to activation of the PPARγ pathway, which upregulates Plin1 to promote lipid droplet formation in hippocampal neurons. This sequestration of fatty acids represents a novel mechanism for reducing neuronal excitability in chronic epilepsy.