Interorgan Coordination of the Murine Adaptive Response to Fasting

Abstract

Starvation elicits a complex adaptive response in an organism.No information on transcriptional regulation of metabolic adaptations is available. We, therefore, studied the gene expression profiles of brain, small intestine, kidney, liver, and skeletal muscle in mice that were subjected to 0 -72 h of fasting. Functional-category enrichment, text mining, and network analyses were employed to scrutinize the overall adaptation, aiming to identify responsive pathways, processes, and networks, and their regulation. The observed transcriptomics response did not follow the accepted "carbohydrate-lipid-protein" succession of expenditure of energy substrates. Instead, these processes were activated simultaneously in different organs during the entire period. The most prominent changes occurred in lipid and steroid metabolism, especially in the liver and kidney. They were accompanied by suppression of the immune response and cell turnover, particularly in the small intestine, and by increased proteolysis in the muscle. The brain was extremely well protected from the sequels of starvation. 60% of the identified overconnected transcription factors were organ-specific, 6% were common for 4 organs, with nuclear receptors as protagonists, accounting for almost 40% of all transcriptional regulators during fasting. The common transcription factors were PPAR␣, HNF4␣, GCR␣, AR (androgen receptor), SREBP1 and -2, FOXOs, EGR1, c-JUN, c-MYC, SP1, YY1, and ETS1. Our data strongly suggest that the control of metabolism in four metabolically active organs is exerted by transcription factors that are activated by nutrient signals and serves, at least partly, to prevent irreversible brain damage.Adapting to starvation requires an interorgan integration of the activity of metabolic pathways to protect the body from an irreversible loss of resources (1, 2), but how the organism integrates these reactions remains largely unknown. Numerous studies on humans, who fasted for 3-6 weeks, have shown that glycogen stores are depleted within a day (3). The decline in circulating glucose and insulin during the next few days (4) induces a transient increase in plasma (essential) amino acids and a concomitant decline in plasma alanine levels due to an increased hepatic extraction for gluconeogenesis (5, 6). Muscle catabolism is a major source of amino acids in this phase. When fasting is continued, muscle protein catabolism declines, and hepatic uptake of amino acids decreases, which is reflected in a decline of endogenous glucose production (6) and urinary nitrogen excretion (4, 7). Lipid catabolism and the (hepatic) production of ketone bodies also increases rapidly and is quantitatively similar after 3 days and 5-6 weeks of starvation (8), but plasma levels increase only gradually to plateau after 4 weeks (4, 9). The associated increase in urinary ketone body (organic-acid) excretion requires a compensatory increase in ammonia production and urinary excretion (4, 7, 10), which is met by an increased renal amino acid uptake and gluconeogenesis (5, 6)...

Detection of Pancreatic Cancer–Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance

“…The decrease in total lipid and TAG in the plasma lipoproteins of Pa04C mice as compared to normal and Panc1 mice likely reflects an increased lipid utilization, presumably from adipose stores, for energy production (fatty acid oxidation and gluconeogenesis from freed glycerol) after glycogen stores were depleted to conserve the body’s protein reserves (39–41). The lower levels of total cholesterol found in plasma lipoproteins of Pa04C tumor bearing mice relative to normal and Panc1 tumor bearing mice indicates the loss of an important precursor used in hormone, bile acid, and vitamin D production.…”

Transcriptome analysis of peripheral blood mononuclear cells in human subjects following a 36 h fast provides evidence of effects on genes regulating inflammation, apoptosis and energy metabolism

“…This is not one of the genes that were previously identified as being affected by fasting in PBMC from human volunteers (Bouwens et al 2007). However, CDKN1A mRNA levels have been reported to increase in a range of tissues (muscle, liver, brain and kidney) in fasted mice (Ebert et al 2010;Hakvoort et al 2011;Mitchell et al 2010;Swindell 2008;Zhang et al 2011). The cluster of genes around CDKN1A in the network includes a number of genes that regulate cell cycling/proliferation and cellular senescence.…”

Erratum: TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop

“…The adaptive response of an organism to food deprivation is associated with major transcriptional and metabolic [1][2][3][4][5] changes and is conserved across evolution 6,7 . One of the most prominent metabolic changes observed during starvation is an increase in lipid catabolism in the liver.…”