PDF(Pubmed)
Abstract：
Nicotinamide mononucleotide (NMN) has emerged as a promising therapeutic intervention for age-related disorders, including type 2 diabetes. In this study, we confirmed the previously observed effects of NMN treatment on glucose uptake and investigated its underlying mechanisms in various tissues and cell lines. Through the most comprehensive proteomic analysis to date, we discovered a series of novel organ-specific effects responsible for glucose uptake as measured by the IPGTT: adipose tissue growing (suggested by increased protein synthesis and degradation and mTOR proliferation signaling upregulation). Notably, we observed the upregulation of thermogenic UCP1, promoting enhanced glucose conversion to heat in intermuscular adipose tissue while showing a surprising repressive effect on mitochondrial biogenesis in muscle and the brain. Additionally, liver and muscle cells displayed a unique response, characterized by spliceosome downregulation and concurrent upregulation of chaperones, proteasomes, and ribosomes, leading to mildly impaired and energy-inefficient protein synthesis machinery. Furthermore, our findings revealed remarkable metabolic rewiring in the brain. This involved increased production of ketone bodies, downregulation of mitochondrial OXPHOS and TCA cycle components, as well as the induction of well-known fasting-associated effects. Collectively, our data elucidate the multifaceted nature of NMN action, highlighting its organ-specific effects and their role in improving glucose uptake. These findings deepen our understanding of NMN\'s therapeutic potential and pave the way for novel strategies in managing metabolic disorders.
摘要：
烟酰胺单核苷酸（NMN）已成为与年龄有关的疾病的有希望的治疗干预措施，包括2型糖尿病。在这项研究中,我们证实了先前观察到的NMN处理对葡萄糖摄取的影响,并研究了其在各种组织和细胞系中的潜在机制.通过迄今为止最全面的蛋白质组学分析，我们发现了一系列新的器官特异性效应,如IPGTT测量的葡萄糖摄取:脂肪组织生长(提示蛋白质合成和降解增加以及mTOR增殖信号上调).值得注意的是,我们观察到产热UCP1的上调,促进肌间脂肪组织中葡萄糖向热的转化增强,同时对肌肉和大脑中的线粒体生物发生表现出惊人的抑制作用.此外,肝脏和肌肉细胞表现出独特的反应，其特征是剪接体下调和伴侣的同时上调，蛋白酶体,和核糖体，导致轻度受损和能源效率低下的蛋白质合成机制。此外，我们的发现揭示了大脑中显著的代谢重新连接.这包括增加酮体的产量，线粒体OXPHOS和TCA循环组分的下调，以及诱导众所周知的禁食相关效应。总的来说，我们的数据阐明了NMN行动的多面性，强调其器官特异性效应及其在改善葡萄糖摄取中的作用。这些发现加深了我们对NMN治疗潜力的理解，并为管理代谢紊乱的新策略铺平了道路。
