Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues
- Equal contributors
1 Institute for Genomics and Bioinformatics, Graz University of Technology, Petersgasse 14, Graz 8010, Austria
2 Institute of Biochemistry, Graz University of Technology, Petersgasse 12/2, Graz 8010, Austria
3 Department of Endocrinology, Diabetes, and Nutrition and Center for Cardiovascular Research (CCR), Charité University Medicine, Hessische Str. 3-4, Berlin 10115, Germany
4 Department of Microbiology, 201 Johnson Pavilion, Perelman School of Medicine University of Pennsylvania, 3610 Hamilton Walk, Philadelphia, PA 19104, USA
5 Pathonomics LLC, Suite 200, 3160 Chestnut St., Philadelphia, PA 19104, USA
6 Penn Bioinformatics Core, University of Pennsylvania, Philadelphia, PA 19104, USA
7 Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
BMC Genomics 2013, 14:758 doi:10.1186/1471-2164-14-758Published: 5 November 2013
Fasting 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.
We 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.
In 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.