Quantitative Analysis of the Physiological Contributions of Glucose to the TCA Cycle

The nutritional source for catabolism in the tricarboxylic acid (TCA) cycle is a fundamental question in metabolic physiology. Limited by data and mathematical analysis, controversy exists. 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. We show that in nearly all circumstances, glucose contributes more than lactate as a substrate to the TCA cycle. This conclusion is verified in different animal strains from different studies and different administrations of 13C glucose, and is extended to multiple tissue types. 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 in mammals. [Display omitted] •A quantitative analysis of central carbon metabolism in physiology is conducted•Glucose is found to be the major nutritional source of the TCA cycle•Lactate has a high exchange flux but lower net circulating flux•Conclusions are robust across many experimental conditions Liu et al. construct a series of models using 13C-isotope tracing data to quantify glucose metabolism in physiology. They analyzed contributions of circulating metabolites to fueling the TCA cycle and provide evidence that glucose is the major nutrient source of the TCA cycle in most situations.