Interorgan coordination of the murine adaptive response to fasting

T.B. Hakvoort, P.D. Moerland, R. Frijters, A. Sokolovic, W.T. Labruyere, J.L. Vermeulen, E. Ver Loren van Themaat, T.M. Breit, F.R. Wittink, A.H. van Kampen, A.J. Verhoeven, W.H. Lamers, M. Sokolovic

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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 hours 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 PPARalpha, HNF4alpha, GCRalpha, AR, 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. 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.
Original languageEnglish
Pages (from-to)16332-16343
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number18
DOIs
Publication statusPublished - 6 May 2011

Keywords

  • FOXO TRANSCRIPTION FACTORS
  • SKELETAL-MUSCLE ATROPHY
  • AMINO ACID METABOLISM
  • GENE-EXPRESSION
  • ADIPONECTIN RECEPTORS
  • PROLONGED STARVATION
  • KETONE-BODIES
  • PROTEIN
  • CHOLESTEROL
  • HOMEOSTASIS

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