The study investigates the role of lactate as a circulating nutrient in the tricarboxylic acid (TCA) cycle in mammalian tissues. Using isotope tracing and metabolic flux analysis, the researchers found that lactate is a significant source of carbon for the TCA cycle, often exceeding the contribution of glucose. In both fed and fasted mice, lactate extensively labels TCA cycle intermediates in all tissues, indicating that lactate is a primary circulating TCA substrate. In genetically engineered cancer tumors, the contribution of lactate to TCA cycle intermediates exceeds that of glucose. The findings suggest that glycolysis and the TCA cycle are uncoupled at the level of lactate, highlighting its importance in energy production and metabolic regulation.The study investigates the role of lactate as a circulating nutrient in the tricarboxylic acid (TCA) cycle in mammalian tissues. Using isotope tracing and metabolic flux analysis, the researchers found that lactate is a significant source of carbon for the TCA cycle, often exceeding the contribution of glucose. In both fed and fasted mice, lactate extensively labels TCA cycle intermediates in all tissues, indicating that lactate is a primary circulating TCA substrate. In genetically engineered cancer tumors, the contribution of lactate to TCA cycle intermediates exceeds that of glucose. The findings suggest that glycolysis and the TCA cycle are uncoupled at the level of lactate, highlighting its importance in energy production and metabolic regulation.