Differential regulation of the immune system in a brain-liver-fatsorgan network during short term fasting.

Abstract Background Different fasting regimens are known to promote health, mitigate chronic immunological disorders, and improve age-related pathophysiological parameters in animals and humans. Indeed, several clinical trials are currently ongoing using fasting as a potential therapy for a wide range of conditions. Fasting alters metabolism by acting as a reset for energy homeostasis, but the molecular mechanisms underlying the beneficial effects of short-term fasting (STF) are still not well understood, particularly at the systems or multi-organ level. Methods We performed RNA-sequencing in nine different organs from mice fed ad libitum (0 hours), or subjected to five different times of fasting (2-22 hours). We applied a combination of multivariate analysis, differential expression analysis, gene ontology and network analysis for an in-depth understanding of the multi-organ transcriptome. We utilized literature mining solutions, LitLab™ and Gene Retriever™, to identify the biological and biochemical terms significantly associated with our experimental gene set which provide additional support and meaning to the experimentally derived gene and protein data. Results We cataloged the transcriptional dynamics within and between organs during STF and discovered differential temporal effects of STF among organs. Using gene ontology enrichment analysis, we identified an organ network sharing 37 common biological pathways perturbed by STF. This network incorporates the brain, liver, interscapular brown adipose tissue, and posterior-subcutaneous white adipose tissue, hence we named it the brain-liver-fats organ network. Using Reactome pathways analysis, we identified the immune system, dominated by T cell regulation processes, as a central and prominent target of systemic modulations during STF in this organ network. The changes we identified in specific immune components point to the priming of adaptive immunity and parallel the fine-tuning of innate immune signaling. Conclusions Our study provides a comprehensive multi-organ transcriptomic profiling of mice subjected to multiple periods of STF and adds new insights into the molecular modulators involved in the systemic immuno-transcriptomic changes that occur during short-term energy loss.