Objective

Fasting 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.

Methods

We 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.

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 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.

中文翻译：

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短期禁食期间脑肝脂肪器官网络中免疫系统的差异调节。

目的

空腹方案可以促进健康，减轻慢性免疫系统疾病，并改善动物和人类与年龄相关的病理生理参数。数项正在进行的临床试验正在将禁食用作各种疾病的潜在疗法。空腹通过重置能量稳态来改变新陈代谢，但是短期空腹（STF）有益作用的分子机制尚未得到很好的理解，特别是在系统或多器官水平。

方法

我们在随意喂食（0 h）或禁食五次（2-22 h）的小鼠的九个器官中进行了RNA测序。我们结合了多变量分析，差异表达分析，基因本体论和网络分析的组合，以深入了解多器官转录组。我们使用文献挖掘解决方案LitLab™和Gene Retriever™来识别与我们的实验基因集显着相关的生物学和生化术语，这为实验衍生的基因和推断的蛋白质数据提供了额外的支持和意义。

结果

我们在STF期间对器官内和器官之间的转录动力学进行了分类，并发现了器官之间STF的时空差异。使用基因本体论富集分析，我们确定了一个器官网络，该网络共享了STF干扰的37条常见生物学途径。该网络包括大脑，肝脏，肩s间褐色脂肪组织和皮下后白色脂肪组织。因此，我们将其命名为“脑肝脂肪器官网络”。使用Reactome途径分析，我们确定了以T细胞调节过程为主的免疫系统，是该器官网络中STF期间系统调节的主要中心目标。我们在特定免疫成分中发现的变化指向适应性免疫的启动，并与先天免疫信号的微调平行。

结论

我们的研究提供了遭受多个STF周期的小鼠的全面多器官转录组分析，并为参与短期能量损失期间发生的全身免疫转录组变化的分子调节剂提供了新见解。