Metabolomics of human fasting: new insights about old questions

Abstract

Since ancient days, human fasting has been performed for religious or political reasons. More recently, fasting has been employed as an effective therapy for weight reduction by obese people, and numerous studies have investigated the physiology of fasting by obese subjects. Well-established fasting markers (butyrates, BCAAs and carnitines) were considered essential energy substitutes after glycogen storage depletion. However, a recently developed metabolomic approach has unravelled previously unappreciated aspects of fasting. Surprisingly, one-third (44) of 120 metabolites investigated increase during 58 h of fasting, including antioxidative metabolites (carnosine, ophthalmic acid, ergothioneine and urates) and metabolites of entire pathways, such as the pentose phosphate pathway. Signalling metabolites (3-hydroxybutyrate and 2-oxoglutarate) and purines/pyrimidines may also serve as transcriptional modulators. Thus, prolonged fasting activates both global catabolism and anabolism, reprogramming metabolic homeostasis.

Keywords: ageing; antioxidant; blood metabolites; metabolomics; prolonged fasting; signalling metabolites.

Figure 1.

Well-established markers for fasting. After exhaustion of glycogen storage by fasting, lipids in human liver and white adipose tissues (WAT) are used as alternative energy sources. During fasting, 3-hydroxybutyrate (3-HB) is one of the most prominently increased metabolites (over 25-fold), which is generated from acetoacetic acid. Traversing the blood–brain barrier (BBB) via the monocarboxylate transporter (MCT), 3-HB is transported into brain, where fatty acids cannot be used for energy generation. Next, branched chain amino acids (BCAAs) are mainly released from muscles, followed by uptake into the TCA pathway, or lipogenesis in liver. Third, elevated acylcarnitines facilitate lipid transport into mitochondria. Abbreviations: HBD (α-Hydroxybutyric acid dehydrogenase), SCOT (succinyl-CoA:3-oxo-acid CoA transferase), Th (mitochondrial thiolase), mCPT1 (mitochondrial Carnitine palmitoyltransferase I).

Figure 2.

Forty-four metabolites that increase during fasting include antioxidants, organic acids and signalling-related compounds. Non-targeted comprehensive metabolomics of whole blood detected increases of one-third (44) of metabolites identified during 58 h of fasting. In addition to metabolites for energy production, antioxidative metabolites were identified as fasting markers, which may combat oxidative stress resulting from enhanced mitochondrial activity. Moreover, signalling metabolites would contribute for remodelling of metabolic homeostasis during fasting. See the text for details. Abbreviations: ET; ergothioneine, OA; ophthalmic acid, PPP; pentose phosphate pathway, 3-HB; 3-hydroxybutyrate and 2-OG; 2-oxoglutarate.