Title | Circulating metabolite homeostasis achieved through mass action. |
Publication Type | Journal Article |
Year of Publication | 2022 |
Authors | Li, X, Hui, S, Mirek, ET, Jonsson, WO, Anthony, TG, Lee, WDong, Zeng, X, Jang, C, Rabinowitz, JD |
Journal | Nat Metab |
Volume | 4 |
Issue | 1 |
Pagination | 141-152 |
Date Published | 2022 Jan |
ISSN | 2522-5812 |
Keywords | Algorithms, 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> |
DOI | 10.1038/s42255-021-00517-1 |
Alternate Journal | Nat Metab |
PubMed ID | 35058631 |
PubMed Central ID | PMC9244777 |
Grant List | DP1 DK113643 / DK / NIDDK NIH HHS / United States R00 DK117066 / DK / NIDDK NIH HHS / United States R01 AA029124 / AA / NIAAA NIH HHS / United States R01 DK109714 / DK / NIDDK NIH HHS / United States |