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

全身代谢动态平衡严重依赖于脂肪组织的功能完整性。线粒体在从营养物质中产生细胞能量方面起着至关重要的作用，并构成了活性氧物种(ROS)的重要来源。尽管肥胖和胰岛素抵抗与白色脂肪组织(WAT)中的线粒体功能障碍有很好的联系，但白色脂肪细胞线粒体对WAT的中枢代谢和分泌功能的贡献在很大程度上仍不清楚。肿瘤蛋白P53是一种转录因子，是细胞应激的主要整合因子。P53处于最佳位置，可以感知全身营养负荷和线粒体功能的变化，并协调适当的转录反应，以减轻潜在的代谢负担。虽然全身性营养超负荷和肥胖被证明导致WAT中P53的激活和细胞衰老的特征，但WAT中P53参与的原因和后果还不完全清楚。该项目基于三个中心假设：H1)营养负荷、线粒体功能和ROS控制白色脂肪细胞中P53的激活；H2)白色脂肪细胞P53的激活决定全身代谢的动态平衡；H3)白色脂肪细胞P53激活的程度和持续时间决定其影响是有益的还是有害的。它追求四个主要目标：O1)确定白色脂肪细胞线粒体功能障碍导致有益或有害影响的程度和持续时间；O2)阐明线粒体功能障碍是否触发了白色脂肪细胞中P53的激活和细胞衰老的特征；03)确定线粒体ROS生成和P53激活如何参与白色脂肪细胞线粒体功能障碍的影响；O4)表征P53激活如何参与白色脂肪细胞线粒体功能障碍引发的转录变化，并确定介导其影响的关键因素。这个项目将促进我们对P53作为代谢调节因子的作用的理解。这将导致确定将营养过载和白色脂肪细胞线粒体功能障碍与全身代谢下降联系起来的关键因素，并为肥胖症和2型糖尿病的治疗提供有希望的靶点。

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.