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Redox-dependent liver gluconeogenesis impacts different intensity exercise in mice.
Takahiro Horiuchi1, Keizo Kaneko2, Shinichiro Hosaka1
1Department of Diabetes, Metabolism and Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Nature Metabolism
|September 18, 2025
Summary
Gluconeogenesis (glucose production) is modulated by lactate and glycerol, impacting exercise intensity. Regulating liver glucose production via cytosolic redox states enhances exercise performance.
Area of Science:
- Metabolic regulation
- Exercise physiology
- Biochemistry
Background:
- Hepatic gluconeogenesis generates glucose from various substrates to meet energy demands.
- Preferential substrate utilization in hepatic gluconeogenesis under different physiological conditions remains poorly understood.
- Understanding these pathways is crucial for optimizing energy metabolism and exercise capacity.
Purpose of the Study:
- To investigate how preferential substrate supplies (lactate and glycerol) modulate hepatic gluconeogenesis.
- To determine the impact of altered gluconeogenesis on high- and low-intensity exercise capacities.
- To explore the role of cytosolic redox state in regulating gluconeogenesis and exercise performance.
Main Methods:
- Generation of liver-specific knockout mouse models for phosphoenolpyruvate carboxykinase 1 (L-Pck1KO) and glycerol kinase (L-GykKO).
- Hepatic expression of NADH oxidase from Lactobacillus brevis (LbNOX) to manipulate cytosolic NAD(H)/NAD+ ratio.
- Assessment of exercise capacity at different intensities in genetically modified and treated mice.
Main Results:
- L-Pck1KO mice showed decreased high-intensity exercise capacity but increased low-intensity capacity, linked to enhanced glycerol gluconeogenesis.
- L-GykKO mice exhibited opposite effects, with enhanced lactate gluconeogenesis and altered exercise capacity.
- Hepatic LbNOX expression boosted gluconeogenesis from redox-dependent substrates and improved exercise performance at both intensities, effects dependent on intact Pck1 and Gyk pathways.
Conclusions:
- Substrate availability and cytosolic redox state, not just enzyme expression, are key regulators of hepatic gluconeogenesis and exercise capacity.
- Targeting hepatic gluconeogenesis through cytosolic redox state modulation offers a potent strategy for enhancing exercise performance.
- This study elucidates a novel mechanism linking liver metabolism to physical endurance across different exercise intensities.
