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1 Division of Biology and Medicine, Brown University, Providence, Rhode Island, United States
2 Institute of Biotechnology, University of Helsinki, Finland
3 Exploratory Medicinal Sciences, Pfizer Global Research and Development, Groton, Connecticut, United States
4 Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut, United States
* To whom correspondence should be addressed. E-mail: marc_tatar{at}brown.edu.
A high-resolution time series of transcript abundance was generated to describe global expression dynamics in response to nutrition in Drosophila. Novel non-parametric change-point statistics revealed that within 7 hours of feeding upon yeast, transcript levels changed significantly for approximately 3,500 genes or 20% of the Drosophila genome. Differences as small as 15% were highly significant and 80% of the changes were less than 1.5-fold. Notably, transcript changes reflected rapid down-regulation of the nutrient-sensing insulin and TOR pathways, shifting of fuel metabolism from lipid to glucose oxidation, and increased purine synthesis, TCA-biosynthetic functions and mitochondria biogenesis. To investigate how nutrition coordinates these transcriptional changes, feeding-induced expression changes were compared with those induced by the insulin-regulated transcription factor dFOXO in Drosophila S2 cells. Remarkably, 28% (995) of the nutrient-responsive genes were regulated by activated dFOXO, including genes of mitochondrial biogenesis and a novel homologue of mammalian PPAR
-coactivator-1 (PGC-1), a transcriptional co-activator implicated in controlling mitochondrial gene expression in mammals. Thus, these data implicate dFOXO as a major coordinator of the transcriptional response to nutrients downstream of insulin, and furthermore, suggest that mitochondria biogenesis is linked to insulin signaling via dFOXO-mediated repression of a PGC-1 homologue.
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