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

Abstract

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.

Innate immune remodeling by short‐term intensive fasting

“…Unlike previous work which primarily focuses on circulating peripheral blood mononuclear cells and lymphocytes (Han et al, 2021;Huang et al, 2020), here we sorted CD45 + leukocytes cells to investigate both the differentials in innate and adaptive immune system. CD45 + cells are composed of myeloid, natural killer cells, T cells, B cells, and plasma cells.…”

“…Additionally, long-term calorie restriction differentially modified the expression of innate and adaptive immunity mediators in the intestine with increased gene expression of most cytokines (Suárez-Souto et al, 2012). A recent study showed that short-term (2-22 h) incomplete fasting in mice has differential transient effects on multiple organs (Huang et al, 2020). There, the authors identified T-cell regulation as a central and prominent target of systemic modulations during short-term fasting.…”

Hormone-controlled cooperative binding of transcription factors drives synergistic induction of fasting-regulated genes

“…The manner by which extracellular signals are integrated and translated in cells to produce a coherent response is poorly understood. Here, we investigated the hepatic fasting response which is heavily reliant on transcriptional regulation ( 14 , 23 , 58 ). This response is controlled by the combinatorial effect of several signals, chief among them are glucagon and glucocorticoids.…”

Extrahepatic factors in hepatic immune regulation

“…The brain and liver bidirectionally communicate via humoral and neural networks ( 177 , 178 ). The neural axis between brain and liver interacts closely with the central nervous system (CNS) via the autonomic nervous system (ANS).…”