Nutritional control of p53 activity and its role in metabolic flexibility

• Applicants: Professor Dr. Tim J. Schulz; Professor Michael Schupp, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Nutritional Sciences
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323196138

The capacity of an organism to adapt utilization of fuel to its availability is termed metabolic flexibility. This is based on the cellular ability to switch between metabolic substrates (glucose, fatty acids, or amino acids) depending on abundance and usage efficiency. Loss of metabolic flexibility impairs energy homeostasis and can induce obesity and its associated co-morbidities. We recently discovered that food withdrawal activates the p53 signaling pathway in liver, adipose tissue, and skeletal muscle. Furthermore, our preliminary data suggest that p53 protein stabilization is required to enable an appropriate fasting response by partitioning energy storage during fed state and by regulating catabolic pathways upon fasting. Our observations add to an emerging metabolic function of p53 in post-mitotic cells, which seems to reach beyond its function as tumor suppressor. The overarching goal of this proposal is to elucidate the mechanisms leading to fasting-mediated p53 stabilization and to delineate tissue-specific responses of p53 to changes in nutrient flux. Therefore, we will characterize inducible, tissue-specific p53 knockout mouse models targeting liver, skeletal muscle, and white and brown adipose tissue. Deploying the complementary know-how of this consortium, in combination with the competence of our collaboration partners, these models will be used to investigate the effects of p53 loss-of-function on the transcriptome, metabolome, and energy metabolism in the respective tissues and its consequence for whole body energy homeostasis during feeding/fasting transitions. The proposed studies will provide novel insights into the mechanism by which p53 regulates metabolic flexibility and may unravel future therapeutic interventions for metabolic diseases.

• DFG Programme: Research Grants
• International Connection: Austria
• Co-Investigator: Professor Dr. Andreas Prokesch