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An Organism-Level Quantitative Flux Model of Energy Metabolism in Mice

Bo Yuan,Will Doxsey,Özlem Tok,Y. Kwon,Karen E. Inouye,Gökhan S. Hotamışlıgil,Sheng Hui

Published 2024 in bioRxiv

ABSTRACT

Mammalian tissues feed on nutrients in the blood circulation. At the organism-level, mammalian energy metabolism comprises of oxidation, storage, interconverting, and releasing of circulating nutrients. Though much is known about the individual processes and nutrients, a holistic and quantitative model describing these processes for all major circulating nutrients is lacking. Here, by integrating isotope tracer infusion, mass spectrometry, and isotope gas analyzer measurement, we developed a framework to systematically quantify fluxes through these metabolic processes for 10 major circulating energy nutrients in mice, resulting in an organism-level quantitative flux model of energy metabolism. This model revealed in wildtype mice that circulating nutrients have more dominant metabolic cycling fluxes than their oxidation fluxes, with distinct partition between cycling and oxidation flux for individual circulating nutrients. Applications of this framework in obese mouse models showed on a per animal basis extensive elevation of metabolic cycling fluxes in ob/ob mice, but not in diet-induced obese mice. Thus, our framework describes quantitatively the functioning of energy metabolism at the organism-level, valuable for revealing new features of energy metabolism in physiological and disease conditions. Highlights A flux model of energy metabolism integrating 13C labeling of metabolites and CO2 Circulating nutrients have characteristic partition between oxidation and storage Circulating nutrients’ total cycling flux outweighs their total oxidation flux Cycling fluxes are extensively elevated in ob/ob but not in diet-induced obese mice Graphical Abstract

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