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

By Susie SY Huang, Melanie Makhlouf, Eman H AbouMoussa, Mayra L Ruiz Tejada Segura, Lisa S Mathew, Kun Wang, Man C Leung, Damien Chaussabel, Darren W. Logan, Antonio Scialdone, Mathieu Garand, Luis R Saraiva

Posted 05 Apr 2020
bioRxiv DOI: 10.1101/2020.04.05.026351 (published DOI: 10.1016/j.molmet.2020.101038)

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. However, 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. Here, we investigated the dynamic gene expression patterns associated with six periods of STF in nine different mouse organs. 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. 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. ### Competing Interest Statement The authors have declared no competing interest. * STF : Short-term fasting OB : olfactory bulb BRN : brain CBL : cerebellum BST : brainstem STM : stomach LIV : liver iBAT : interscapular brown adipose tissue pgWAT : perigonadal white adipose tissue psWAT : posterior-subcutaneous white adipose tissue HVG : highly-variable genes log2(x+1) NC : log2 expression values HCA : hierarchical clustering analysis FDR : false discovery rate DEGs : differentially expressed genes FC : fold change log2FC : log2 fold change GO : Gene Ontology subcDEGs : sub-clustered DEGs LitLabTM : Acumenta Literature Lab MeSH : Medical Subject Headings GH : growth hormone IGF : insulin-like growth factors BDNF : brain-derived neurotropic factor NE : norepinephrine

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