Quantitative analysis of the physiological contributions of glucose to the TCA cycle

The carbon source for catabolism in vivo is a fundamental question in metabolic physiology. Limited by data and rigorous mathematical analysis, many controversial statements exist on the metabolic sources for carbon usage in the tricarboxylic acid (TCA) cycle under physiological settings. Using isotope-labeling data in vivo across several experimental conditions, we construct multiple models of central carbon metabolism and develop methods based on metabolic flux analysis (MFA) to solve for the preferences of glucose, lactate, and other nutrients used in the TCA cycle across many tissues. We show that in nearly all circumstances, glucose contributes more than lactate as a nutrient source for the TCA cycle. This conclusion is verified in different animal strains, different administrations of 13C glucose, and is extended to multiple tissue types after considering multiple nutrient sources. Thus, this quantitative analysis of organismal metabolism defines the relative contributions of nutrient fluxes in physiology, provides a resource for analysis of in vivo isotope tracing data, and concludes that glucose is the major nutrient used for catabolism in mammals.