Mammalian tissues are fuelled by circulating nutrients, including glucose, amino acids, and various intermediary metabolites. Under aerobic conditions, glucose is generally assumed to be burned fully by tissues via the tricarboxylic acid cycle (TCA cycle) to carbon dioxide. Alternatively, glucose can be catabolized anaerobically via glycolysis to lactate, which is itself also a potential nutrient for tissues1 and tumours2,3,4,5. The quantitative relevance of circulating lactate or other metabolic intermediates as fuels remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice, and find that lactate can be a primary source of carbon for the TCA cycle and thus of energy. Intravenous infusions of 13C-labelled nutrients reveal that, on a molar basis, the circulatory turnover flux of lactate is the highest of all metabolites and exceeds that of glucose by 1.1-fold in fed mice and 2.5-fold in fasting mice; lactate is made primarily from glucose but also from other sources. In both fed and fasted mice, 13C-lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis reveals that during the fasted state, the contribution of glucose to tissue TCA metabolism is primarily indirect (via circulating lactate) in all tissues except the brain. In genetically engineered lung and pancreatic cancer tumours in fasted mice, the contribution of circulating lactate to TCA cycle intermediates exceeds that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumours.
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We thank C. Wright for providing the Ptf1a-cre mice; M. Sander for help and advice; and the members of the Rabinowitz laboratory and J. Baur, Z. Arany, and M. Lazar for scientific discussions. This work was supported by NIH grants 1DP1DK113643, R01 CA163591, R01 CA130893, K22 CA190521, R01 CA186043, R35 CA197699, R50 CA211437, P30 CA072720 (Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey), and 5P30 DK019525. In addition, it was supported by a Stand Up To Cancer–Cancer Research UK–Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (grant number: SU2C-AACR-DT-20-16). S.H. is a Merck Fellow of the Life Sciences Research Foundation. C.J. is a postdoctoral fellow of the American Diabetes Association.