Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 105, Issue 4, Pages -Publisher
ENDOCRINE SOC
DOI: 10.1210/clinem/dgz266
Keywords
Capillary electrophoresis; metabolomics; succinate; exercise; liver; cAMP
Categories
Funding
- TrygFonden
- Capital Region of Denmark
- Danish National Research Foundation [DNRF55]
- DD2 -the Danish Center for Strategic Research in Type 2 Diabetes (the Danish Council for Strategic Research) [09-067009, 09-075724]
- Danish Diabetes Academy - Novo Nordisk Foundation
- Augustinus Foundation
- German Federal Ministry of Education and Research (BMBF) [01GI0925]
- Sino-German Center for Research Promotion (DFG) [GZ 753, LE 1391/1-1]
- Sino-German Center for Research Promotion (NSFC) [GZ 753]
- National Natural Science Foundation of China [21435006, 21874130]
- Alexander von Humboldt Foundation
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Context: The liver is crucial to maintain energy homeostasis during exercise. Skeletal muscle-derived metabolites can contribute to the regulation of hepatic metabolism. Objective: We aim to elucidate which metabolites are released from the working muscles and taken up by the liver in exercising humans and their potential influence on hepatic function. Methods: In two separate studies, young healthy men fasted overnight and then performed an acute bout of exercise. Arterial-to-venous differences of metabolites over the hepato-splanchnic bed and over the exercising and resting leg were investigated by capillary electrophoresis- and liquid chromatography-mass spectrometry metabolomics platforms. Liver transcriptome data of exercising mice were analyzed by pathway analysis to find a potential overlap between exercise-regulated metabolites and activators of hepatic transcription. Results: During exercise, hepatic O-2 uptake and CO2 delivery were increased two-fold. In contrast to all other free fatty acids (FFA), those FFA with 18 or more carbon atoms and a high degree of saturation showed a constant release in the liver vein and only minor changes by exercise. FFA 6:0 and 8:0 were released from the working leg and taken up by the hepatosplanchnic bed. Succinate and malate showed a pronounced hepatic uptake during exercise and were also released from the exercising leg. The transcriptional response in the liver of exercising mice indicates the activation of HIF-, NRF2-, and cAMP-dependent gene transcription. These pathways can also be activated by succinate. Conclusion: Metabolites circulate between working muscles and the liver and may support the metabolic adaption to exercise by acting both as substrates and as signaling molecules.
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