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Post-fast refeeding enhances intestinal stem cell mediated regeneration and tumorigenesis through mTORC1 signaling and polyamine

ABSTRACT: For more than a century, fasting regimens have been shown to improve health, lifespan, and tissue regeneration in diverse model organisms and humans. However, important questions remain regarding how fasting and refeeding cycles stimulate stem cell output and how this influences their role in early tumor formation. Here, we demonstrate that in the mammalian intestine, a short 24-hour fast followed by a 24-hour refeeding period (that is, post-fast refeeding) and not fasting itself elevates the stemness program and regenerative capacity of Lgr5+ intestinal stem cells (ISCs). Furthermore, loss of the tumor suppressor APC in post-fast refed ISCs significantly boosts tumor incidence in the small intestine and colon compared to those in the fasted or ad libitum fed states. Mechanistically, robust induction of insulin-PI3K-mTORC1 signaling as well as elevated intestinal polyamines level increase protein synthesis in post-fast refed ISCs to mediate these changes as inhibition of mTORC1, polyamine, or protein synthesis abrogate the regenerative or tumorigenic effects of post-fast refeeding. Thus, our data indicate that post-fast refeeding leads to a burst not only in stem cell-driven regeneration but also in tumorigenicity and that careful consideration be given to fast-refeeding cycles when planning diet-based strategies.

ORGANISM(S): Mus musculus

PROVIDER: GSE192482 | GEO | 2023/08/08

REPOSITORIES: GEO

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Project description:Delayed access to feed following hatching has been associated with reduction in growth performance in chicks. However, the gene networks within the hypothalamus that regulate feed intake and metabolism, and the effects of fasting on those pathways are not well understood. The present experiment evaluated global hypothalamic gene expression in neonatal chicks using the Arizona Gallus gallus 20.7K Oligo Array v1.0 to elucidate genes and pathways regulated by feeding, fasting, and refeeding. Ten groups of chicks were sampled over four days post-hatch, including: control (at hatch), 24h fed, 24h fasted, 48h fed, 48h fasted, 48h fasted then 4h refed, 72h fed, 48h fasted then 24h refed, 96h fed, and 48h fasted then 48h refed. Non-esterified fatty acids were elevated, and triglycerides were decreased in fasted chicks at 24 and 48h, indicating that fasting induced physiological changes. Hypothalamic samples were collected from 16 chicks per group, and total RNA was extracted and pooled for hybridization (n=4). Expression patterns of selected genes were confirmed by quantitative real-time PCR. Two-fold differences in gene expression were detected in 1,272 genes between treatment groups, and of those, 119 genes were significantly (P<0.05) different. Assignment of gene ontology terms to the significant genes resulted in 34 different categories of biological processes, with 24% of genes participating in signal transduction, transport, or metabolic processes. Genes that were upregulated during fasting (and confirmed by qPCR) include FK506BP51, which is involved in the formation of steroid receptor complexes, and deiodinase type II, which is responsible for converting the thyroid hormone T4 into T3. Confirmed genes, downregulated due to fasting, included proopiomelanocortin and fatty acid binding protein 7. Other regulated genes were identified that play a role in feeding and obesity in other species, such as relaxin 3 and adrenergic receptor-β2. Further analysis of differentially regulated genes could provide new information regarding the role of the hypothalamus in feed intake and metabolism. Keywords: Metabolic perturbation Ten experimental groups with 4 replicates each were analyzed. A reference RNA design was used for this microarray. Equal amounts of amplified RNA (aRNA) from all samples were pooled and labeled with the Alexa 647 to create the reference pool. Each individual sample was labeled with Alexa 555. Each slide was hybridized with both the reference pool and one sample.

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Post-fast refeeding enhances intestinal stem cell mediated regeneration and tumorigenesis through mTORC1 signaling and polyamine

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