{"title":"Redox-dependent liver gluconeogenesis impacts different intensity exercise in mice.","authors":"Takahiro Horiuchi,Keizo Kaneko,Shinichiro Hosaka,Kenji Uno,Seitaro Tomiyama,Kei Takahashi,Maya Yamato,Akira Endo,Hiroto Sugawara,Yohei Kawana,Yoichiro Asai,Shinjiro Kodama,Junta Imai,Seiya Mizuno,Satoru Takahashi,Atsushi Takasaki,Hiraku Ono,Koutaro Yokote,Rae Maeda,Yuki Sugiura,Hideki Katagiri","doi":"10.1038/s42255-025-01373-z","DOIUrl":null,"url":null,"abstract":"Hepatic gluconeogenesis produces glucose from various substrates to meet energy demands. However, how these substrates are preferentially used under different conditions remains unclear. Here, we show that preferential supplies of lactate and glycerol modulate hepatic gluconeogenesis, thereby impacting high-intensity and low-intensity exercise capacities, respectively. We find that liver-specific knockout of phosphoenolpyruvate carboxykinase 1 (L-Pck1KO), which blocks gluconeogenesis from lactate, decreases high-intensity exercise capacity but increases low-intensity exercise capacity by enhancing gluconeogenesis from glycerol. Conversely, liver-specific knockout of glycerol kinase (L-GykKO), which inhibits glycerol-derived gluconeogenesis, induces the opposite effects by enhancing gluconeogenesis from lactate. Given that these compensatory steps depend on NAD+-mediated oxidation in the cytosol, we hepatically expressed NADH oxidase from Lactobacillus brevis (LbNOX) to decrease the cytosolic [NADH]/[NAD+] ratio. We find that hepatic LbNOX expression enhances gluconeogenesis from both redox-dependent substrates and increases exercise capacities at both intensities. Importantly, LbNOX-induced enhancement of high-intensity and low-intensity exercise capacities is abolished in L-Pck1KO and L-GykKO mice, respectively. Therefore, supplies of gluconeogenic substrates and cytosolic redox states, rather than altered enzyme expressions, modulate hepatic gluconeogenesis and exercise capacity at different intensities. Globally, this study shows that regulating hepatic gluconeogenesis through cytosolic redox states is a potent strategy for increasing exercise performance.","PeriodicalId":19038,"journal":{"name":"Nature metabolism","volume":"9 1","pages":""},"PeriodicalIF":20.8000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature metabolism","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s42255-025-01373-z","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
Abstract
Hepatic gluconeogenesis produces glucose from various substrates to meet energy demands. However, how these substrates are preferentially used under different conditions remains unclear. Here, we show that preferential supplies of lactate and glycerol modulate hepatic gluconeogenesis, thereby impacting high-intensity and low-intensity exercise capacities, respectively. We find that liver-specific knockout of phosphoenolpyruvate carboxykinase 1 (L-Pck1KO), which blocks gluconeogenesis from lactate, decreases high-intensity exercise capacity but increases low-intensity exercise capacity by enhancing gluconeogenesis from glycerol. Conversely, liver-specific knockout of glycerol kinase (L-GykKO), which inhibits glycerol-derived gluconeogenesis, induces the opposite effects by enhancing gluconeogenesis from lactate. Given that these compensatory steps depend on NAD+-mediated oxidation in the cytosol, we hepatically expressed NADH oxidase from Lactobacillus brevis (LbNOX) to decrease the cytosolic [NADH]/[NAD+] ratio. We find that hepatic LbNOX expression enhances gluconeogenesis from both redox-dependent substrates and increases exercise capacities at both intensities. Importantly, LbNOX-induced enhancement of high-intensity and low-intensity exercise capacities is abolished in L-Pck1KO and L-GykKO mice, respectively. Therefore, supplies of gluconeogenic substrates and cytosolic redox states, rather than altered enzyme expressions, modulate hepatic gluconeogenesis and exercise capacity at different intensities. Globally, this study shows that regulating hepatic gluconeogenesis through cytosolic redox states is a potent strategy for increasing exercise performance.
期刊介绍:
Nature Metabolism is a peer-reviewed scientific journal that covers a broad range of topics in metabolism research. It aims to advance the understanding of metabolic and homeostatic processes at a cellular and physiological level. The journal publishes research from various fields, including fundamental cell biology, basic biomedical and translational research, and integrative physiology. It focuses on how cellular metabolism affects cellular function, the physiology and homeostasis of organs and tissues, and the regulation of organismal energy homeostasis. It also investigates the molecular pathophysiology of metabolic diseases such as diabetes and obesity, as well as their treatment. Nature Metabolism follows the standards of other Nature-branded journals, with a dedicated team of professional editors, rigorous peer-review process, high standards of copy-editing and production, swift publication, and editorial independence. The journal has a high impact factor, has a certain influence in the international area, and is deeply concerned and cited by the majority of scholars.