ELOVL6: A Key Factor in the Gender Differences of Olanzapine-Induced Weight Gain

Background: This study investigates the role of ELOVL6 in the weight gain induced by olanzapine and the mechanisms underlying the female-specific response. Methods: An olanzapine-induced weight gain model in SD rats was developed. Transcriptome sequencing and metabolomics identified genes and metabolites linked to female-specific weight gain. Validation was conducted in HL7702 cells, and DNA pulldown, ChIP-qPCR, and molecular docking explored the molecular mechanism. A genetic polymorphism association study was also performed. Results: Female rats showed more pronounced weight gain compared to males following olanzapine treatment. Transcriptomic and metabolomics analyses revealed that olanzapine significantly upregulates hepatic ELOVL6 expression and long-chain fatty acid synthesis in females. Inhibition of ELOVL6 restores the elevated levels of the lipid, SREBP-1c and FAS induced by olanzapine. The transcription factor HNF-3α is implicated in ELOVL6 regulation, and some olanzapine metabolites can directly interact with HNF-3α. Furthermore, a single-nucleotide polymorphism (SNP) at the ELOVL6 promoter -1427 bp correlates with weight gain in female patients. Conclusions: Olanzapine metabolites interact with HNF-3α, enhancing ELOVL6 transcription. The upregulated ELOVL6 promotes long-chain fatty acid synthesis via the SREBP-1c/FAS pathway, contributing to female-specific weight gain.