In 2017, a study published in Nature revealed that lactate, a byproduct of glucose metabolism, serves as a primary source of carbon for the tricarboxylic acid (TCA) cycle in mammals. The research, led by Sheng Hui and colleagues, used isotopic tracing to measure the turnover flux of circulating metabolites in mice. They found that lactate has a higher circulatory turnover flux than glucose, especially under fasting conditions. Lactate is primarily derived from glucose but also from other sources. In both fed and fasted mice, lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis showed that in fasted mice, glucose contributes to tissue TCA metabolism indirectly via lactate, except in the brain. In genetically engineered lung and pancreatic cancer tumors, the contribution of circulating lactate to TCA cycle intermediates exceeded that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. The study demonstrated that glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumors. The findings highlight the importance of lactate as a metabolic intermediate and its role in energy metabolism, particularly in cancer. The study also showed that lactate turnover flux reflects the whole-body pyruvate production rate, multiplied by the fraction of tissue pyruvate excreted as lactate. The research provides new insights into the metabolic interplay between tissues and the role of lactate in energy production and cancer metabolism.In 2017, a study published in Nature revealed that lactate, a byproduct of glucose metabolism, serves as a primary source of carbon for the tricarboxylic acid (TCA) cycle in mammals. The research, led by Sheng Hui and colleagues, used isotopic tracing to measure the turnover flux of circulating metabolites in mice. They found that lactate has a higher circulatory turnover flux than glucose, especially under fasting conditions. Lactate is primarily derived from glucose but also from other sources. In both fed and fasted mice, lactate extensively labels TCA cycle intermediates in all tissues. Quantitative analysis showed that in fasted mice, glucose contributes to tissue TCA metabolism indirectly via lactate, except in the brain. In genetically engineered lung and pancreatic cancer tumors, the contribution of circulating lactate to TCA cycle intermediates exceeded that of glucose, with glutamine making a larger contribution than lactate in pancreatic cancer. The study demonstrated that glycolysis and the TCA cycle are uncoupled at the level of lactate, which is a primary circulating TCA substrate in most tissues and tumors. The findings highlight the importance of lactate as a metabolic intermediate and its role in energy metabolism, particularly in cancer. The study also showed that lactate turnover flux reflects the whole-body pyruvate production rate, multiplied by the fraction of tissue pyruvate excreted as lactate. The research provides new insights into the metabolic interplay between tissues and the role of lactate in energy production and cancer metabolism.