Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats
Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction‐associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to die...
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eLife Sciences Publications Ltd
2025-02-01
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| Online Access: | https://elifesciences.org/articles/98427 |
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| author | Hong Yang Cheng Zhang Woonghee Kim Mengnan Shi Metin Kiliclioglu Cemil Bayram Ismail Bolar Özlem Özdemir Tozlu Cem Baba Nursena Yuksel Serkan Yildirim Shazia Iqbal Jihad Sebhaoui Ahmet Hacımuftuoglu Matthias Uhlen Jan Boren Hasan Turkez Adil Mardinoglu |
| author_facet | Hong Yang Cheng Zhang Woonghee Kim Mengnan Shi Metin Kiliclioglu Cemil Bayram Ismail Bolar Özlem Özdemir Tozlu Cem Baba Nursena Yuksel Serkan Yildirim Shazia Iqbal Jihad Sebhaoui Ahmet Hacımuftuoglu Matthias Uhlen Jan Boren Hasan Turkez Adil Mardinoglu |
| author_sort | Hong Yang |
| collection | DOAJ |
| description | Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction‐associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD. |
| format | Article |
| id | doaj-art-687913462aa3453080b514fa4f6a2683 |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-687913462aa3453080b514fa4f6a26832025-02-11T12:11:02ZengeLife Sciences Publications LtdeLife2050-084X2025-02-011310.7554/eLife.98427Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in ratsHong Yang0https://orcid.org/0009-0002-0414-2471Cheng Zhang1https://orcid.org/0000-0002-3721-8586Woonghee Kim2Mengnan Shi3Metin Kiliclioglu4Cemil Bayram5Ismail Bolar6Özlem Özdemir Tozlu7Cem Baba8Nursena Yuksel9Serkan Yildirim10Shazia Iqbal11Jihad Sebhaoui12Ahmet Hacımuftuoglu13Matthias Uhlen14Jan Boren15Hasan Turkez16Adil Mardinoglu17https://orcid.org/0000-0002-4254-6090Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, SwedenScience for Life Laboratory, KTH Royal Institute of Technology, Stockholm, SwedenScience for Life Laboratory, KTH Royal Institute of Technology, Stockholm, SwedenScience for Life Laboratory, KTH Royal Institute of Technology, Stockholm, SwedenDepartment of Pathology, Veterinary Faculty , Atatürk University, Erzurum, TurkiyeDepartment of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, TurkiyeDepartment of Pathology, Veterinary Faculty , Atatürk University, Erzurum, TurkiyeDepartment of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, TurkiyeDepartment of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, TurkiyeDepartment of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, TurkiyeDepartment of Pathology, Veterinary Faculty , Atatürk University, Erzurum, TurkiyeTrustlife Labs Drug Research and Development Center, Istanbul, TurkiyeTrustlife Labs Drug Research and Development Center, Istanbul, TurkiyeDepartment of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, TurkiyeScience for Life Laboratory, KTH Royal Institute of Technology, Stockholm, SwedenDepartment of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, SwedenDepartment of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, TurkiyeScience for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United KingdomExcessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction‐associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.https://elifesciences.org/articles/98427MAFLDJNKsucroseJNK-IN-5Amulti-tissue transcriptome |
| spellingShingle | Hong Yang Cheng Zhang Woonghee Kim Mengnan Shi Metin Kiliclioglu Cemil Bayram Ismail Bolar Özlem Özdemir Tozlu Cem Baba Nursena Yuksel Serkan Yildirim Shazia Iqbal Jihad Sebhaoui Ahmet Hacımuftuoglu Matthias Uhlen Jan Boren Hasan Turkez Adil Mardinoglu Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats eLife MAFLD JNK sucrose JNK-IN-5A multi-tissue transcriptome |
| title | Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats |
| title_full | Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats |
| title_fullStr | Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats |
| title_full_unstemmed | Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats |
| title_short | Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats |
| title_sort | multi tissue network analysis reveals the effect of jnk inhibition on dietary sucrose induced metabolic dysfunction in rats |
| topic | MAFLD JNK sucrose JNK-IN-5A multi-tissue transcriptome |
| url | https://elifesciences.org/articles/98427 |
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