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.