Nutritional control of p53 activity and its role in metabolic flexibility

p53 活性的营养控制及其在代谢灵活性中的作用

• 批准号: 323196138
• 负责人: Professor Dr. Tim J. Schulz
• 金额: --
• 依托单位: Institut für Pharmakologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/323196138?language=en
• 关键词: Nutritional; control; p53; activity; its

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.

生物体适应燃料利用的能力称为代谢灵活性。这是基于细胞根据丰度和使用效率在代谢底物（葡萄糖、脂肪酸或氨基酸）之间切换的能力。代谢灵活性的丧失损害能量稳态，并可诱导肥胖及其相关的合并症。我们最近发现，食物戒断激活了肝脏、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蛋白的稳定是必要的，使一个适当的禁食反应，通过分区能量储存在进食状态和调节分解代谢途径后禁食。我们的观察增加了一个新兴的代谢功能的p53在有丝分裂后的细胞，这似乎超出了其作为肿瘤抑制因子的功能。该提案的总体目标是阐明导致禁食介导的p53稳定的机制，并描绘p53对营养通量变化的组织特异性反应。因此，我们将表征针对肝脏、骨骼肌、白色和棕色脂肪组织的诱导型、组织特异性p53基因敲除小鼠模型。利用该联盟的互补技术，结合我们合作伙伴的能力，这些模型将用于研究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在进食/禁食过渡期间对全身能量稳态的影响。拟议的研究将为p53调节代谢灵活性的机制提供新的见解，并可能揭示未来代谢疾病的治疗干预措施。

项目成果

Insulin Directly Regulates the Circadian Clock in Adipose Tissue

胰岛素直接调节脂肪组织的昼夜节律时钟

• DOI: 10.2337/db20-0910
• 发表时间: 1999
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Pivovarova-Ramich;Murahovschi;Grudziecki;Nikiforova;Osterhoff;Gottmann;Gogebakan;Sticht;Schupp;Schürmann;Rudovich;Pfeiffer;A. F. H.
• 通讯作者: A. F. H.