Tohoku University clarifies that the substrates for hepatic gluconeogenesis change according to exercise intensity — Running slowly uses "glycerol," running quickly uses "lactate"

A research group led by Lecturer Keizo Kaneko, Specially Appointed Researcher Takahiro Horiuchi, and Professor Hideki Katagiri of Tohoku University Graduate School of Medicine announced that the substrates used for gluconeogenesis in the liver differ according to exercise intensity. Through experiments with mice, they found that the liver performs gluconeogenesis using glycerol as a substrate during low-intensity exercise such as slow running, and lactate during high-intensity exercise such as running quickly, enabling the continuation of exercise. This is expected to lead to an increase in exercise performance and developing preventive and therapeutic approaches for obesity and sarcopenia. The findings were published in the journal Nature Metabolism on September 18.

Animals have mechanisms to maintain constant blood glucose levels in the body. In addition to obtaining glucose by breaking down carbohydrates from food, gluconeogenesis occurs in the liver using endogenous substrates during periods of sudden consumption such as fasting or exercise. The typical substrates for gluconeogenesis during exercise are lactate produced by muscle activity and glycerol produced by fat breakdown, but the differences between them were unclear.

In this study, the research group investigated which substrates are used and how they are utilized during exercise.

When mice were made to run slowly or quickly using a treadmill, compared with resting mice, glycerol increased in the blood of mice running slowly, while lactate increased in mice running quickly. This suggested the possibility that different substrates are used for each type of exercise.

To verify this, the group created knockout mice that cannot perform gluconeogenesis from glycerol (glycerol gluconeogenesis-deficient mice) and mice that cannot perform gluconeogenesis from lactate (lactate gluconeogenesis-deficient mice). In turn, the group had each perform the two types of exercise.

As a result, when glycerol gluconeogenesis-deficient mice were made to run slowly and lactate gluconeogenesis-deficient mice were made to run quickly, the running duration was shortened in both cases. This revealed that substrates are selectively used according to exercise intensity: lactate for vigorous exercise and glycerol for light exercise.

On the other hand, when glycerol gluconeogenesis-deficient mice were made to run quickly and lactate gluconeogenesis-deficient mice were made to run slowly, the running duration increased in both cases.

Understanding this mechanism could potentially improve exercise capacity, so they analyzed the metabolic processes behind them.

To achieve this, they focused on the oxidation-reduction cycle in which NAD⁺, which promotes metabolic flow, becomes NADH and then returns to NAD⁺. They also investigated the possibility that blocking one pathway for either glycerol or lactate would supply NAD⁺ to only one pathway and improve exercise capacity. Finally, they increased expression of NAD⁺ in the livers of wild-type mice

As a result, when the wild-type mice without gene intervention were made to run slowly, the running duration increased by 50%. When they were made to run quickly, the running duration increased by 40%. Exercise capacity improved regardless of exercise intensity, and the training effects on the wild-type mice exceeded the previously reported effects on mice. This suggests the possibility of improving exercise capacity through liver-targeted approaches in the future.

Going forward, the researchers aim to clarify the mechanisms by which substrates are switched and to develop methods that can lead to increasing exercise performance and prevention of obesity and sarcopenia.

Journal Information
Publication: Nature Metabolism
Title: Redox-dependent liver gluconeogenesis impacts different intensity exercise in mice
DOI: 10.1038/s42255-025-01373-z