Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle

Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle

eLife

10.7554/eLife.107332.3

https://doi.org/10.7554/elife.107332.3

Yibo Fan, Senuri De Silva, Nishat I Tabassum, Xiangyuan Peng, Vernise JT Lim, Xiangru Cheng, Keshava K Datta, Rohan Lowe, Terrance G Johns, Mark P Mattson, Suresh Mathivanan, Christopher G Sobey, Eitan Okun, Yong U Liu, Guobing Chen, Mitchell Kim Peng Lai, Dong-Gyu Jo, Jayantha Gunaratne, Thiruma V Arumugam

17 April 2026

Fan, Y., De Silva, S., Tabassum, N. I., Peng, X., Lim, V. J., Cheng, X., Datta, K. K., Lowe, R., Johns, T. G., Mattson, M. P., Mathivanan, S., Sobey, C. G., Okun, E., Liu, Y. U., Chen, G., Lai, M. K. P., Jo, D.-G., Gunaratne, J., & Arumugam, T. V. (2026). Uncovering shared and tissue-specific molecular adaptations to intermittent fasting in liver, brain, and muscle. eLife, 14. CLOCKSS. https://doi.org/10.7554/elife.107332.3

Intermittent fasting (IF) has emerged as a powerful dietary intervention with profound metabolic benefits, yet the tissue-specific molecular mechanisms underlying these effects remain poorly understood. In this study, we employed comprehensive proteomics and transcriptomics analysis to investigate the systemic and organ-specific adaptations to IF in male C57BL/6 mice. Following a 16 hr daily fasting regimen (IF16) over 4 months, IF reduced blood glucose, HbA1c, and cholesterol levels while increasing ketone bodies, indicative of enhanced metabolic flexibility. Proteomic profiling of the liver, skeletal muscle, and cerebral cortex revealed tissue-specific responses, with the liver exhibiting the most pronounced changes, including upregulation of pathways involved in fatty acid oxidation, ketogenesis, and glycan degradation, and downregulation of steroid hormone and cholesterol metabolism. In muscle, IF enhanced pyruvate metabolism, fatty acid biosynthesis, and AMPK signaling, while suppressing oxidative phosphorylation and thermogenesis. The cerebral cortex displayed unique adaptations, with upregulation of autophagy, PPAR signaling, and metabolic pathways, and downregulation of TGF-beta and p53 signaling, suggesting a shift toward energy conservation and stress resilience. Notably, Serpin A1c emerged as the only protein commonly upregulated across all three tissues, highlighting its potential role in systemic adaptation to IF. Integrative transcriptomic and proteomic analyses revealed partial concordance between mRNA and protein expression, underscoring the complexity of post-transcriptional regulation. Shared biological signaling processes were identified across tissues, suggesting unifying mechanisms linking metabolic changes to cellular communication. Our findings reveal both conserved and tissue-specific responses by which IF may optimize energy utilization, enhance metabolic flexibility, and promote cellular resilience.

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There was no specific funding for the research done

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https://oar.a-star.edu.sg/communities-collections/articles/23400

2050-084X

Institute of Molecular and Cell Biology

https://doi.org/10.7554/elife.107332.3