Circulating metabolite homeostasis achieved through mass action.

TitleCirculating metabolite homeostasis achieved through mass action.
Publication TypeJournal Article
Year of Publication2022
AuthorsLi, X, Hui, S, Mirek, ET, Jonsson, WO, Anthony, TG, Lee, WDong, Zeng, X, Jang, C, Rabinowitz, JD
JournalNat Metab
Volume4
Issue1
Pagination141-152
Date Published2022 01
ISSN2522-5812
KeywordsAlgorithms, Amino Acids, Animals, Biomarkers, Citric Acid Cycle, Energy Metabolism, Glucose, Homeostasis, Male, Metabolome, Metabolomics, Mice, Mice, Knockout, Models, Biological, Oxidation-Reduction
Abstract

<p>Homeostasis maintains serum metabolites within physiological ranges. For glucose, this requires insulin, which suppresses glucose production while accelerating its consumption. For other circulating metabolites, a comparable master regulator has yet to be discovered. Here we show that, in mice, many circulating metabolites are cleared via the tricarboxylic acid cycle (TCA) cycle in linear proportionality to their circulating concentration. Abundant circulating metabolites (essential amino acids, serine, alanine, citrate, 3-hydroxybutyrate) were administered intravenously in perturbative amounts and their fluxes were measured using isotope labelling. The increased circulating concentrations induced by the perturbative infusions hardly altered production fluxes while linearly enhancing consumption fluxes and TCA contributions. The same mass action relationship between concentration and consumption flux largely held across feeding, fasting and high- and low-protein diets, with amino acid homeostasis during fasting further supported by enhanced endogenous protein catabolism. Thus, despite the copious regulatory machinery in mammals, circulating metabolite homeostasis is achieved substantially through mass action-driven oxidation.</p>

DOI10.1038/s42255-021-00517-1
Alternate JournalNat Metab
PubMed ID35058631
Grant ListR01 DK109714 / DK / NIDDK NIH HHS / United States
R00 DK117066 / DK / NIDDK NIH HHS / United States
DP1 DK113643 / DK / NIDDK NIH HHS / United States