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

abstract: ...Background 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. Results We investigated the dynamic changes of liver gene expression and serum parameters of mice at several time points during a 48hour 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. Conclusions 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.

...BMC Genomics BMC Genomics BMC Genomics 1471-2164 BioMed Central 24191950 3907060 1471-2164-14-758 10.1186/1471-2164-14-758 Research Article Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues Schupp Michael 3 michael.schupp@charite.de Chen Fang 4 chenfang@upenn.edu Briggs Erika R 7 erikabr@mail.med.upenn.edu Rao Shilpa 6 rshilpa@mail.med.upenn.edu Pelzmann Helmut J 1 2 helmut.pelzmann@student.tugraz.at Pessentheiner Ariane R 1 2

... 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. Conclusions 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. Fasting Starvation Nutrient deprivation Adipose tissue p53 signaling Ddit4 Lipolysis Background Fasting processes are evolutionarily highly conserved adaptive responses to food deprivation in all organisms. Mammals follow a day/night pattern that includes a daily resting period during which the body is in a fasted

..., and skeletal muscle utilizing microarray technology followed by a host of bioinformatic analyses. Interesting outcomes from the fasted adipose tissue data include a strong enrichment of upregulated genes coding for proteins that regulate transcription as well as apoptosis-related genes. A major finding is the identification of the p53 signaling pathway as a common mediator of the fasting response in all three investigated tissues. Driven by these results we focused on the p53-target gene Ddit4, which was upregulated by fasting in all three tissues. Our experiments showed that, in cultured adipocytes, Ddit4 is inducible by p53 activation and its ectopic expression is sufficient to augment lipolysis. Therefore we describe a new molecular component in the fasting-response downstream of p53. Results and discussion Kinetics of serum parameters and liver gene expression in mice during a 48hour fasting period Despite a considerable amount of knowledge about the mechanisms of fasting response in

...) pathways. Values are log2 transformed. White dots mark highest expression between the 3 tissues. Table 2 Fold difference in expression (fasted/fed) of transcripts regulated in WAT, LIV, and SM by fasting UNIQID NAME WAT LIV SM UNIQID NAME WAT LIV SM NM_029083 Ddit4 7.86 4.46 17.72 NM_133904 Acacb 2.74 2.05 1.40 NM_007669 Cdkn1a 2.02 10.20 4.43 NM_024479 Wbscr27 1.48 1.43 2.02 NM_007679 Cebpd 3.36 2.29 8.54 NM_016972 Slc7a8 2.03 1.72 1.74 NM_010220 Fkbp5 3.40 5.84 4.19 NM_019873 Fkbpl 1.33 1.33 2.03

... average expression across WAT, LIV, and SM: Ddit4 , Cdkn1a , and Cebpd), none of which have previously been functionally described in the context of fasting in mice, as well as Per1 and Fasn , known responders to food deprivation and thereby positive controls (Figure 5 ). Per1 is an essential regulator in the core clock machinery of circadian rhythm [ 10 , 68 ] and, in LIV and AT at the beginning of the light phase, it was previously shown that its expression is higher in fasting compared to control

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Gene: DDIT4 - DNA-damage-inducible transcript 4 - (NCBI)

Protein : 3lq9

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