Dissecting p53/Foxo1 cooperativity in obesity and fasting

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

Obesity often associates with comorbidities such as type 2 diabetes, cardiovascular disease, and cancer. While pharmacological means to curtail obesity are only beginning to emerge, fasting and caloric restriction remain a proven intervention. The underlying molecular mechanisms are still rather unexplored and appear to go far beyond a simple reduction in energy intake. The transcription factors p53 and Foxo1 are independently known to coordinate genetic programs during feeding/fasting transitions. Our previously published and unpublished preliminary data suggest a tight interplay between p53 and Foxo1 signalling in liver, adipose tissue, and skeletal muscle. Moreover, we found a previously unreported direct interaction of p53 and Foxo1 as well as co-regulatory interdependencies in a tissue specific manner. We hypothesize that a multi-layered nuclear interaction between p53 and FOXO1 regulates feeding/fasting transitions in liver, adipose tissue, and skeletal muscle, and propose that this interaction is required for the salutary effects of cyclic fasting on the mitigation of obesity and its associated co-morbidities. Hence, we plan to investigate the molecular and structural nature of the p53/FOXO1 interaction (direct/indirect, trans/cis), as well as the intricacies of tissue-specific co-regulation of each other and on the level of activation of common target genes and pathways. We combine standard molecular biology methods (luciferase assays, co-IPs) with sophisticated state-of-the-art approaches (NMR spectroscopy, fluorescence anisotropy, isothermal titration calorimetry) to map intra- and inter-molecular protein-protein interactions. We further use novel tissue-specific, inducible p53 and/or Foxo1 knock out mouse models with an established protocol of fasting-mediated obesity intervention, in liaison with genome-wide detection of fasting-selective enhancers/promoters (PRO-seq) and transcription factor binding (ChIP-seq) to unravel the specific modes and consequences of p53/FOXO1 interaction in cis. Comprehensive metabolic phenotyping and differential comparison of p53 and/or Foxo1 knock out animals will reveal insight into the impact of the p53/FOXO1-axis on fasting/feeding transitions to tackle obesity. Understanding tissue-specific transcriptional networks is imperative to enable the design of fasting regimens and mimetics for preventive, personalized medicine that targets hallmarks of obesity and the metabolic syndrome. Hence, as both p53 and FOXO1 are pharmacological actionable, our results are poised to infuse innovations in the field of obesity research.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Professor Dr. Andreas Prokesch