Dissecting p53/Foxo1 cooperativity in obesity and fasting

Obesity is often associated with diseases such as type 2 diabetes, cardiovascular disease (collectively called the metabolic syndrome), and cancer. While pharmacological means to curtail obesity are available, fasting and caloric restriction remain important life-style interventions for the long-term weight maintenance. However, the underlying molecular mechanisms of their beneficial health effects are still rather unexplored and appear to go far beyond a simple reduction in energy intake or weight loss. The proteins p53 and Foxo1 regulate gene activity by binding to DNA. They are independently known to coordinate cellular programs in dependence of nutrient abundances. Our previously published and our unpublished preliminary data suggest a tight interplay between p53 and Foxo1 signalling in liver, adipose tissue, and skeletal muscle in various nutrition states. On the molecular level 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 as well as the intricacies of tissue-specific co-regulation of each other and on the level of activation of common pathways. To investigate this, we combine standard molecular biology methods with sophisticated state-of-the- art approaches to map intra- and inter-molecular protein-protein interactions. We will develop novel cell-specific, inducible preclinical models to modify p53 and/or Foxo1 levels. Through comprehensive metabolic characterisation, their interactions during of fasting-mediated obesity intervention will be elucidated. We will also unravel the specific modes and consequences of p53/FOXO1 interaction on the DNA level. Thus, understanding tissue-specific gene regulatory 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. Primary researchers involved Assoc.-Prof. Dr. Andreas Prokesch (FWF - lead): Medical University of Graz, Graz, Austria Prof. Dr. Michael Schupp (DFG): Charité Berlin, Berlin, Germany Prof. Dr. Tim J. Schulz (DFG): German Institute of Human Nutrition Potsdam-Rehbruecke, Germany