PHARMACEUTICALS · Published 2026-08-04 · DOI 10.3390/ph19081223
Keke Che, Dejuan Li, Lu Liu, Yanyan Zhang, Xuemei Liu, Changhua Hu
<b>Background:</b> This study investigates the role of <i>ELOVL6</i> in the weight gain induced by olanzapine and the mechanisms underlying the female-specific response. <b>Methods:</b> 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. <b>Results:</b> Female rats showed more pronounced weight gain compared to males following olanzapine treatment. Transcriptomic and metabolomics analyses revealed that olanzapine significantly upregulates hepatic <i>ELOVL6</i> expression and long-chain fatty acid synthesis in females. Inhibition of <i>ELOVL6</i> restores the elevated levels of the lipid, <i>SREBP-1c</i> and <i>FAS</i> induced by olanzapine. The transcription factor <i>HNF-3α</i> is implicated in <i>ELOVL6</i> regulation, and some olanzapine metabolites can directly interact with <i>HNF-3α</i>. Furthermore, a single-nucleotide polymorphism (SNP) at the <i>ELOVL6</i> promoter -1427 bp correlates with weight gain in female patients. <b>Conclusions:</b> Olanzapine metabolites interact with <i>HNF-3α</i>, enhancing <i>ELOVL6</i> transcription. The upregulated <i>ELOVL6</i> promotes long-chain fatty acid synthesis via the <i>SREBP-1c</i>/<i>FAS</i> pathway, contributing to female-specific weight gain.
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Che, K., Li, D., Liu, L., et al. (2026). ELOVL6: A Key Factor in the Gender Differences of Olanzapine-Induced Weight Gain. PHARMACEUTICALS. https://doi.org/10.3390/ph19081223