Mammalian tissues are fueled not only by food constituents such as glucose, but also by various intermediary metabolites, the quantitative significance of which remains unclear. Here we systematically examine the fluxes of circulating metabolites in mice. We find that circulatory turnover flux of lactate exceeds those of glucose and other metabolites, and 13C-lactate extensively labels TCA cycle intermediates in all tissues. Moreover, in mouse models of cancer, the contribution of lactate to tumor TCA cycle intermediates exceeds that of glucose. Quantitatively flux analysis shows that glucose contributes to TCA metabolism primarily via circulating lactate in both tissues and tumors. Thus, glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumors.

Sheng Hui is a postdoctoral fellow in the Lewis-Sigler Institute for Integrative Genomics at Princeton University. He is currently working on whole-body energy metabolism in the lab of Josh Rabinowitz. Dr. Hui received his BSc and MPhil degrees in Physics from Hong Kong Baptist University, where he worked on theoretical analysis of metabolic networks in Lei-Han Tang’s group. He received his PhD in Biophysics in 2014 from University of California, San Diego. Working in Terry Hwa’s lab, his doctoral research focused on understanding strategies of coordinating protein expression and metabolism in bacteria. The long-term scientific goal of Dr. Hui is to gain a holistic understanding of mammalian metabolism by taking an integrative approach of animal experimentation, isotopic tracing with mass spectrometry, and quantitative modeling. Dr. Hui is a Merck fellow of the Life Sciences Research Foundation.