Abstract
Obesity impairs metabolic flexibility—the capacity to adapt to fluctuating energy demands. Emerging evidence suggests that dietary interventions, particularly time-restricted feeding (TRF), may help restore this flexibility. In this study, we demonstrate that feeding upregulates PRMT3 and asymmetric dimethylarginine (ADMA)-containing proteins via insulin–pAKT signaling, while fasting reduces their expression. Pharmacological inhibition of PRMT3 attenuates diet-induced obesity (DIO) and enhances adipocyte glycolysis in male mice. Mechanistically, PRMT3 drives the expression of citrate transporter SLC25A1 during feeding through direct arginine methylation. A 16:8 TRF regimen normalizes PRMT3 and ADMA levels while suppressing SLC25A1 expression. Notably, PRMT3 inhibition recapitulates the metabolic benefits of 16:8 TRF and improves metabolic flexibility. Furthermore, adipocyte-specific deletion of Slc25a1 in male mice protects against DIO and enhances insulin sensitivity. Collectively, these findings identify PRMT3-mediated arginine methylation in vWAT as a nutrient-responsive regulatory axis that impairs metabolic flexibility in obesity, which is a potential therapeutic target.
Data availability
All data are available in the main text or the supplementary materials. Source data are provided with this paper. RNA-seq and Metabolomics data has been updated as Supplementary Data. Source data are provided in this paper.
Code availability
No new code has been generated in this study.
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Acknowledgements
We thank all members of the Jia and Zhang laboratories for helpful discussions. We thank CAM-SU for excellent guidance and assistance with experiments performed in this study. Research support was provided by STI2030-Major Projects (2021ZD0203400 to Y.Z.), National Natural Science Foundation of China (32100944 to Z.J. and 32271206 to Y.Z.), Natural Science Foundation of Jiangsu Province (BK20210715 to Z.J.), Gusu Innovation and Entrepreneur Leading Talents project (ZXL2023200 to Z.J.), Natural Science Foundation of Jiangsu Province (No. BK20255001), Ministry of Science and Technology (2018YFA0801102 to Y.D.). YZ’s lab was supported by the Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases.
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Z.J. and Y.Z. conceived the study, Z.J. and A.V. wrote the manuscript. Z.J., Y.Z., A.V., and Z.H. designed experiments. Z.H., X.L., X.C., You, Q.C., H.Z., M.D., and S.L. performed experiments. Z.J., Z.H., and K.C. visualized and curated the data. Y.L., K.C., Y.F., L.S., L.W., T.S., S.K., and Y.D. contributed reagents/materials/analysis tools. Z.J., Y.Z., and A.V. edited the manuscript.
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Huang, Z., Liu, X., Chen, X. et al. PRMT3-mediated post-translational adaptation to fasting regulates metabolic flexibility. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68883-6
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DOI: https://doi.org/10.1038/s41467-026-68883-6
