Abstract
ObjectiveFasting regimens can promote health, mitigate chronic immunological disorders, and improve age-related pathophysiological parameters in animals and humans. Several ongoing clinical trials are using fasting as a potential therapy for various 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 not well understood, particularly at the systems or multiorgan level. MethodsWe performed RNA-sequencing in nine organs from mice fed ad libitum (0 h) or subjected to fasting five times (2–22 h). We applied a combination of multivariate analysis, differential expression analysis, gene ontology, and network analysis for an in-depth understanding of the multiorgan transcriptome. We used literature mining solutions, LitLab™ and Gene Retriever™, to identify the biological and biochemical terms significantly associated with our experimental gene set, which provided additional support and meaning to the experimentally derived gene and inferred protein data. ResultsWe 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. ConclusionsOur study provides a comprehensive multiorgan transcriptomic profiling of mice subjected to multiple periods of STF and provides new insights into the molecular modulators involved in the systemic immunotranscriptomic changes that occur during short-term energy loss.
Highlights
Dietary restriction refers to an intervention that can range from chronic but minor reduction in calorie intake to periods of repeated cycles of short-term fasting (STF) and, in humans, those lasting more than 48h [1]
Transcriptome profiling across multiple organs in the fasted mice To investigate the global gene expression dynamics associated with STF, we used mRNA-seq to profile the transcriptomes of nine organs obtained from mice subjected to six different STF duration (0, 2, 8, 12, 18 and 22 hours of fasting; n=3 per time point; Fig. 1a)
The nine organs profiled were: olfactory bulb (OB), brain (BRN, which includes the telencephalon and diencephalon), cerebellum (CBL), brainstem (BST, which consists of the mesencephalon, pons, and myelencephalon), stomach (STM), liver (LIV), interscapular brown adipose tissue, perigonadal white adipose tissue, and posteriorsubcutaneous white adipose tissue
Summary
Dietary restriction refers to an intervention that can range from chronic but minor reduction in calorie intake to periods of repeated cycles of short-term fasting (STF) and, in humans, those lasting more than 48h [1]. These various forms of reduction in food consumption have many beneficial effects on health, including weight reduction, amelioration of autoimmune diseases, and increased lifespan [2,3].
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