Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice
Objective: Recent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as “metaflammation,” which contributes to obesity and type 2 diabetes. In...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-09-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820300831 |
| _version_ | 1819049675674615808 |
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| author | Debora Collotta William Hull Raffaella Mastrocola Fausto Chiazza Alessia Sofia Cento Catherine Murphy Roberta Verta Gustavo Ferreira Alves Giulia Gaudioso Francesca Fava Magdi Yaqoob Manuela Aragno Kieran Tuohy Christoph Thiemermann Massimo Collino |
| author_facet | Debora Collotta William Hull Raffaella Mastrocola Fausto Chiazza Alessia Sofia Cento Catherine Murphy Roberta Verta Gustavo Ferreira Alves Giulia Gaudioso Francesca Fava Magdi Yaqoob Manuela Aragno Kieran Tuohy Christoph Thiemermann Massimo Collino |
| author_sort | Debora Collotta |
| collection | DOAJ |
| description | Objective: Recent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as “metaflammation,” which contributes to obesity and type 2 diabetes. In this study, we investigated the effects of the JAK1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine high-fat-high sugar diet model. Methods: Male C57BL/6 mice were fed with a control normal diet (ND) or a high-fat-high sugar diet (HD) for 22 weeks. A sub-group of HD fed mice was treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks (HD + Bar). Results: HD feeding resulted in obesity, insulin-resistance, hypercholesterolemia and alterations in gut microbial composition. The metabolic abnormalities were dramatically reduced by chronic baricitinib administration. Treatment of HD mice with baricitinib did not change the diet-induced alterations in the gut, but restored insulin signaling in the liver and skeletal muscle, resulting in improvements of diet-induced myosteatosis, mesangial expansion and associated proteinuria. The skeletal muscle and renal protection were due to inhibition of the local JAK2-STAT2 pathway by baricitinib. We also demonstrated that restored tissue levels of JAK2-STAT2 activity were associated with a significant reduction in cytokine levels in the blood. Conclusions: In summary, our data suggest that the JAK2-STAT2 pathway may represent a novel candidate for the treatment of diet-related metabolic derangements, with the potential for EMA- and FDA-approved JAK inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications. |
| first_indexed | 2024-12-21T11:35:55Z |
| format | Article |
| id | doaj.art-0bd346f6d49542e6a6efd0bfa718368a |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-21T11:35:55Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-0bd346f6d49542e6a6efd0bfa718368a2022-12-21T19:05:27ZengElsevierMolecular Metabolism2212-87782020-09-0139Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in miceDebora Collotta0William Hull1Raffaella Mastrocola2Fausto Chiazza3Alessia Sofia Cento4Catherine Murphy5Roberta Verta6Gustavo Ferreira Alves7Giulia Gaudioso8Francesca Fava9Magdi Yaqoob10Manuela Aragno11Kieran Tuohy12Christoph Thiemermann13Massimo Collino14Department of Drug Science and Technology, University of Turin, Turin, ItalyQueen Mary University of London, Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UKDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyQueen Mary University of London, Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UKDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyEdmund Mach Foundation, San Michele all'Adige, ItalyEdmund Mach Foundation, San Michele all'Adige, ItalyQueen Mary University of London, Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UKDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyEdmund Mach Foundation, San Michele all'Adige, ItalyQueen Mary University of London, Center for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK; Corresponding author. Queen Mary University London, The William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, UK.Department of Drug Science and Technology, University of Turin, Turin, Italy; Corresponding author. Department of Drug Science and Technology, University of Turin, via P. Giuria 9, 10125 Torino, Italy.Objective: Recent evidence suggests the substantial pathogenic role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the development of low-grade chronic inflammatory response, known as “metaflammation,” which contributes to obesity and type 2 diabetes. In this study, we investigated the effects of the JAK1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine high-fat-high sugar diet model. Methods: Male C57BL/6 mice were fed with a control normal diet (ND) or a high-fat-high sugar diet (HD) for 22 weeks. A sub-group of HD fed mice was treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks (HD + Bar). Results: HD feeding resulted in obesity, insulin-resistance, hypercholesterolemia and alterations in gut microbial composition. The metabolic abnormalities were dramatically reduced by chronic baricitinib administration. Treatment of HD mice with baricitinib did not change the diet-induced alterations in the gut, but restored insulin signaling in the liver and skeletal muscle, resulting in improvements of diet-induced myosteatosis, mesangial expansion and associated proteinuria. The skeletal muscle and renal protection were due to inhibition of the local JAK2-STAT2 pathway by baricitinib. We also demonstrated that restored tissue levels of JAK2-STAT2 activity were associated with a significant reduction in cytokine levels in the blood. Conclusions: In summary, our data suggest that the JAK2-STAT2 pathway may represent a novel candidate for the treatment of diet-related metabolic derangements, with the potential for EMA- and FDA-approved JAK inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications.http://www.sciencedirect.com/science/article/pii/S2212877820300831MetaflammationBaricitinibHigh-fat-high sugar dietJAK2-STAT2 pathwayInsulin resistance |
| spellingShingle | Debora Collotta William Hull Raffaella Mastrocola Fausto Chiazza Alessia Sofia Cento Catherine Murphy Roberta Verta Gustavo Ferreira Alves Giulia Gaudioso Francesca Fava Magdi Yaqoob Manuela Aragno Kieran Tuohy Christoph Thiemermann Massimo Collino Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice Molecular Metabolism Metaflammation Baricitinib High-fat-high sugar diet JAK2-STAT2 pathway Insulin resistance |
| title | Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice |
| title_full | Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice |
| title_fullStr | Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice |
| title_full_unstemmed | Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice |
| title_short | Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice |
| title_sort | baricitinib counteracts metaflammation thus protecting against diet induced metabolic abnormalities in mice |
| topic | Metaflammation Baricitinib High-fat-high sugar diet JAK2-STAT2 pathway Insulin resistance |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820300831 |
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