Tumor protein p53 at the interface of white adipocyte mitochondrial function and systemic metabolic homeostasis

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Systemic metabolic homeostasis is critically dependent on the functional integrity of adipose tissue. Mitochondria play a crucial role in the generation of cellular energy from nutrients and constitute an important source of reactive oxygen species (ROS). Despite a well-documented association of obesity and insulin resistance with mitochondrial dysfunction in white adipose tissue (WAT), the contribution of white adipocyte mitochondria to central metabolic and secretory functions of WAT remains largely uncharted. Tumor protein p53 is a transcription factor that acts as the cardinal integrator of cellular stress. p53 is optimally positioned to sense alterations in systemic nutrient load and mitochondrial function and orchestrate appropriate transcriptional responses to alleviate potential metabolic burdens. Although systemic nutrient overload and obesity were shown to result in an activation of p53 and characteristics of cellular senescence in WAT, the causes and consequences of WAT p53 engagement are only incompletely understood. This project is based on three central hypotheses: H1) nutrient load, mitochondrial function, and ROS control p53 activation in white adipocytes; H2) white adipocyte p53 activation determines systemic metabolic homeostasis; H3) the degree and duration of white adipocyte p53 activation decide whether its effects are beneficial or detrimental. It pursues four main objectives: O1) to determine what degrees and durations of white adipocyte mitochondrial dysfunction result in either beneficial or detrimental effects; O2) to elucidate whether mitochondrial dysfunction triggers p53 activation and characteristics of cellular senescence in white adipocytes; O3) to establish how mitochondrial ROS production and p53 activation contribute to the effects of white adipocyte mitochondrial dysfunction; O4) to characterize how p53 activation contributes to the transcriptional changes triggered by white adipocyte mitochondrial dysfunction and identify key factors that mediate its effects. This project will advance our understanding of the role of p53 as a metabolic regulator. It will result in the identification of key factors that link nutrient overload and white adipocyte mitochondrial dysfunction to systemic metabolic decline and yield promising targets for the treatment of obesity and type 2 diabetes mellitus.