The carbon source for catabolism in vivo is a fundamental question in metabolic physiology. Limited by data and rigorous mathematical analysis, controversy exists over the nutritional sources for carbon 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 from different studies, 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 for catabolism in mammals.

Measurements of metabolic reactions under physiological conditions has been a challenging problem. In a recent issue of Nature, Bartman et al. designed an isotope-labeling-based method to measure tricarboxylic acid (TCA) fluxes in normal tissue and tumors in mice. The method revealed that primary tumors exhibit lower TCA fluxes compared with normal tissue, consistent with current knowledge. They also found that solid tumors generally exhibit lower energy production rates.