Abstract
Background
Obesity is a serious multifactorial disease that involves epigenetic mechanisms like DNA methylation. Tyrosine kinase inhibitors (TKIs), originally synthesized and approved for cancer therapy, have recently been linked to the regulation of obesity. We evaluated whether LPM4870108, a small-molecule TKI with antitumor efficacy, contributes to obesity
Methods
LPM4870108 (TKI) was administered orally to rats at 0, 1.25, 2.5, or 5.0 mg/kg (for 28 days, twice daily). Body weights (BWs) and food intake were recorded daily. After 28 days of administration, ventromedial hypothalamus (VMH) tissues were collected for whole-genome transcriptomic and methylation sequencing to identify candidate genes. The mRNA expression and promoter methylation of candidate genes were analyzed by real-time RT-PCR and pyrosequencing, respectively. Protein levels of DNA methyltransferases (DNMTs) were determined by Western blot.
Results
LPM4870108 treatment substantially increased food intake and BW. Whole-genome transcriptomic and methylation profiling identified 415 differentially expressed genes (DEGs) and 124,935 differentially methylated regions (DMRs) within the VMH of LPM4870108-treated rats. The transcriptomic results were combined with whole-genome methylation sequencing data, followed by further verification via RT-PCR and pyrosequencing, through which the obesity-related candidate gene arginine vasopressin (AVP) was identified. Among all DEGs, AVP showed the most prominent change, with a negative association between its promoter methylation and mRNA expression level. Reduced protein expression of DNA methyltransferase 3A (DNMT3A) in the VMH was also detected in LPM4870108-treated rats.
Conclusions
These findings indicate that LPM4870108-stimulated hyperphagia and weight gain were associated with DNA hypomethylation and concomitant upregulation of the AVP gene
LPM4870108, tyrosine kinase inhibitors; VMH, ventromedial hypothalamus; RRBS, reduced representation bisulfite sequencing; AVP, arginine vasopressin; DNMT, DNA methyltransferases
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Acknowledgements
The authors thank Sangon Biotech (Shanghai, China) for the support in transcriptome data analysis
Funding
This work was supported by the Natural Science Foundation of Shandong Province (No. ZR2024QH124) and the Initial Scientific Research Fund of Yantai University (Grant no. SM22B181)
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Author notes
These authors contributed equally: Jingwei Tian, Sijin Duan
Authors and Affiliations
School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, PR China
Baiyang Yuan, Xuan Jin, Chunmei Li, Hongbo Wang, Jingwei Tian & Sijin Duan
State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, PR China
Jingwei Tian
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Contributions
BY: Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization. XJ: Conceptualization, Methodology, Formal analysis, Investigation, Writing – review & editing, Supervision. CL: Methodology, Investigation, Data curation. HW: Formal analysis, Resources, Writing – review & editing, Supervision. JT: Resources, Project administration. SD: Conceptualization, Resources, Project administration. All authors read and approved the final manuscript.
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All experimental procedures in this study were conducted in accordance with the National Institutes of Health Guidelines for Care and Use of Laboratory Animals and all animal protocols were approved by the Laboratory Animals Care and Use Committee of Yantai University (YTU20210635)
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Yuan, B., Jin, X., Li, C. et al. Integrative multi-omics analysis of DNA methylome and transcriptome in a tyrosine kinase inhibitor LPM4870108-induced rat model of obesity.
Int J Obes (2026). https://doi.org/10.1038/s41366-026-02157-5
Received:05 December 2025
Revised:16 June 2026
Accepted:01 July 2026
Published:10 July 2026
Version of record:10 July 2026
DOI
:https://doi.org/10.1038/s41366-026-02157-5
