Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues

Abstract

BackgroundFasting induces specific molecular and metabolic adaptions in most organisms. In biomedical research fasting is used in metabolic studies to synchronize nutritional states of study subjects. Because there is a lack of standardization for this procedure, we need a deeper understanding of the dynamics and the molecular mechanisms in fasting.ResultsWe investigated the dynamic changes of liver gene expression and serum parameters of mice at several time points during a 48 hour fasting experiment and then focused on the global gene expression changes in epididymal white adipose tissue (WAT) as well as on pathways common to WAT, liver, and skeletal muscle. This approach produced several intriguing insights: (i) rather than a sequential activation of biochemical pathways in fasted liver, as current knowledge dictates, our data indicates a concerted parallel response; (ii) this first characterization of the transcriptome signature of WAT of fasted mice reveals a remarkable activation of components of the transcription apparatus; (iii) most importantly, our bioinformatic analyses indicate p53 as central node in the regulation of fasting in major metabolic tissues; and (iv) forced expression of Ddit4, a fasting-regulated p53 target gene, is sufficient to augment lipolysis in cultured adipocytes.ConclusionsIn summary, this combination of focused and global profiling approaches provides a comprehensive molecular characterization of the processes operating during fasting in mice and suggests a role for p53, and its downstream target Ddit4, as novel components in the transcriptional response to food deprivation.

Intermittent metabolic switching, neuroplasticity and brain health

“…Animals on the CR diets consume all their daily food allotment within a 4 hour time window and therefore fast for 20 hours; during the last half of the fasting period, plasma ketone concentrations are elevated and the plasma glucose concentration remains low. The illustrations are based on data in several different studies, including those in REFS 184–187. Although plasma β-hydroxybutyrate levels are rarely measured in exercise studies, there are data showing that bouts of vigorous exercise (running or swimming) do elevate circulating ketone levels in rodents 188,189 .…”

Transcriptional dynamics of immune, growth and stress related genes in skeletal muscle of the fine flounder ( Paralichthys adpersus) during different nutritional statuses

“…Moreover, REED1 has been shown to increase the mRNA and protein levels in mammalian muscle cells when treated with dexamethasone, a synthetic glucocorticoid (Wang et al, 2006). This was also observed in rats treated with corticosterone (McGhee et al, 2009) and when subjected to periods of fasting (Schupp et al, 2013). The present results are in line with these previously published data, suggesting that these genes are associated with the stress response, which would be in addition to promoting atrophy, in the skeletal muscle of fine flounder during different nutritional statuses.…”

Is REDD1 a Metabolic Éminence Grise ?

“…In addition to REDD1-mediated effects on lipogenesis, a separate study by Schupp and coworkers also revealed that forced expression of REDD1 was sufficient to induce lipolysis in cultured C3H10T1/2 adipocytes, as evidenced by increased glycerol and free fatty acid release [56]. Interestingly, this REDD1-driven enhancement in lipolysis did not coincide with significant alterations to lipolytic genes, such as those encoding adipose triglyceride lipase ( ATGL ) and hormone sensitive lipase ( HSL ) [56]. Therefore, given the emerging evidence for REDD1 in the modulation of lipid homeostasis, further work will be required to determine those factors that can mediate the regulatory actions of REDD1 on lipolytic and lipogenic processes, particularly in vivo .…”

“…Further evidence supporting a role for REDD1 in mediating the biological actions of glucocorticoids was revealed by work demonstrating protection against the atrophic effects of topical glucocorticoid application in skin cells of REDD1-knockout mice [54], as well as the prevention of dexamethasone-induced skeletal muscle atrophy in REDD1-null mice [55]. Alternatively, elevated REDD1 mRNA abundance in white adipose tissue, liver, and skeletal muscle of fasted mice has been suggested to be induced by the activation of p53, as evidenced by the ability of the p53 activator nutlin-3 to increase REDD1 mRNA abundance in C3H10T1/2 adipocytes [56]. Therefore, changes in the activity of distinct factors, such as glucocorticoid levels and p53 activity, may underlie altered REDD1 expression in different nutritional states, with further analysis required to establish how these may impact insulin action and other metabolic parameters.…”

“…Accordingly, REDD1 may be implicated in the control of lipogenic pathways through its ability to modulate insulin signalling and, in particular, the activity of downstream PKB/Akt targets, such as the transcription factor sterol regulatory element binding protein-1 (SREBP-1), which has a crucial role in lipid homeostasis by inducing the expression of genes, such as those encoding acetyl-CoA carboxylase ( ACC ) and fatty acid synthase 82, 83. In addition to REDD1-mediated effects on lipogenesis, a separate study by Schupp and coworkers also revealed that forced expression of REDD1 was sufficient to induce lipolysis in cultured C3H10T1/2 adipocytes, as evidenced by increased glycerol and free fatty acid release [56]. Interestingly, this REDD1-driven enhancement in lipolysis did not coincide with significant alterations to lipolytic genes, such as those encoding adipose triglyceride lipase ( ATGL ) and hormone sensitive lipase ( HSL ) [56].…”