Diverse metabolic reactions activated during 58-hr fasting are revealed by non-targeted metabolomic analysis of human blood

During human fasting, metabolic markers, including butyrates, carnitines, and branched-chain amino acids, are upregulated for energy substitution through gluconeogenesis and use of stored lipids. We performed non-targeted, accurate semiquantitative metabolomic analysis of human whole blood, plasma, and red blood cells during 34-58 hr fasting of four volunteers. During this period, 44 of ~130 metabolites increased 1.5~60-fold. Consistently fourteen were previously reported. However, we identified another 30 elevated metabolites, implicating hitherto unrecognized metabolic mechanisms induced by fasting. Metabolites in pentose phosphate pathway are abundant, probably due to demand for antioxidants, NADPH, gluconeogenesis and anabolic metabolism. Global increases of TCA cycle-related compounds reflect enhanced mitochondrial activity in tissues during fasting. Enhanced purine/pyrimidine metabolites support RNA/protein synthesis and transcriptional reprogramming, which is promoted also by some fasting-related metabolites, possibly via epigenetic modulations. Thus diverse, pronounced metabolite increases result from greatly activated catabolism and anabolism stimulated by fasting. Anti-oxidation may be a principal response to fasting.

在人体禁食状态下，包括丁酸酯类、肉碱类与支链氨基酸在内的代谢标志物会上调，以通过糖异生途径与利用储存脂质实现能量替代。本研究对4名志愿者开展34~58小时的禁食处理，并对其全血、血浆及红细胞进行非靶向精准半定量代谢组学分析。在此期间，约130种检测到的代谢物中，有44种丰度上调1.5~60倍；其中14种代谢物的变化已被既往研究报道。但本研究还新鉴定出30种丰度上调的代谢物，这提示存在此前未被阐明的禁食诱导代谢调控机制。磷酸戊糖途径相关代谢物丰度显著升高，这可能源于机体对抗氧化剂、烟酰胺腺嘌呤二核苷酸磷酸（NADPH）、糖异生底物以及合成代谢过程的需求。三羧酸循环（TCA cycle）相关化合物的全局丰度升高，反映了禁食状态下机体组织线粒体活性的增强。嘌呤与嘧啶类代谢物丰度升高，可支持RNA与蛋白质合成及转录重编程；部分禁食相关代谢物或可通过表观遗传调控途径，进一步促进这一过程。综上，多种代谢物出现显著丰度变化，源于禁食所激活的强烈分解代谢与合成代谢过程；而抗氧化应答或为机体应对禁食的核心反应之一。