Nutritional control of p53 activity and its role in metabolic flexibility

生物体使燃料的利用适应其可获得性的能力称为代谢灵活性。这是基于细胞根据代谢底物(葡萄糖、脂肪酸或氨基酸)的丰度和使用效率在代谢底物之间切换的能力。代谢灵活性的丧失会破坏能量平衡，并可能导致肥胖及其相关的共病。我们最近发现，停止进食会激活肝脏、脂肪组织和骨骼肌中的P53信号通路。此外，我们的初步数据表明，P53蛋白的稳定是通过在摄食状态下分配能量存储和调节禁食后的分解代谢途径来实现适当的禁食反应。我们的观察增加了p53在有丝分裂后细胞中的一种新的代谢功能，这似乎超出了其作为肿瘤抑制因子的功能。这项建议的首要目标是阐明导致禁食介导的P53稳定的机制，并描述P53对营养通量变化的组织特异性反应。因此，我们将以肝脏、骨骼肌以及白色和棕色脂肪组织为靶点，建立可诱导的、组织特异性的p53基因敲除小鼠模型。利用这个联盟的互补技术，结合我们合作伙伴的能力，这些模型将被用来研究P53功能丧失对相应组织中转录组、代谢组和能量代谢的影响及其对摄食/禁食转变期间全身能量平衡的影响。拟议的研究将为P53调节代谢灵活性的机制提供新的见解，并可能揭示未来对代谢性疾病的治疗干预。

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.