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Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice.
Mol Metab. 2020 09; 39:101009.MM

Abstract

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.

Authors+Show Affiliations

Department of Drug Science and Technology, University of Turin, Turin, Italy.Queen 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.Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.Department of Drug Science and Technology, University of Turin, Turin, Italy.Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.Queen 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.Department of Drug Science and Technology, University of Turin, Turin, Italy.Department of Drug Science and Technology, University of Turin, Turin, Italy.Edmund Mach Foundation, San Michele all'Adige, Italy.Edmund Mach Foundation, San Michele all'Adige, Italy.Queen 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.Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.Edmund Mach Foundation, San Michele all'Adige, Italy.Queen 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. Electronic address: c.thiemermann@qmul.ac.uk.Department of Drug Science and Technology, University of Turin, Turin, Italy. Electronic address: massimo.collino@unito.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32413585

Citation

Collotta, Debora, et al. "Baricitinib Counteracts Metaflammation, Thus Protecting Against Diet-induced Metabolic Abnormalities in Mice." Molecular Metabolism, vol. 39, 2020, p. 101009.
Collotta D, Hull W, Mastrocola R, et al. Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice. Mol Metab. 2020;39:101009.
Collotta, D., Hull, W., Mastrocola, R., Chiazza, F., Cento, A. S., Murphy, C., Verta, R., Alves, G. F., Gaudioso, G., Fava, F., Yaqoob, M., Aragno, M., Tuohy, K., Thiemermann, C., & Collino, M. (2020). Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice. Molecular Metabolism, 39, 101009. https://doi.org/10.1016/j.molmet.2020.101009
Collotta D, et al. Baricitinib Counteracts Metaflammation, Thus Protecting Against Diet-induced Metabolic Abnormalities in Mice. Mol Metab. 2020;39:101009. PubMed PMID: 32413585.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice. AU - Collotta,Debora, AU - Hull,William, AU - Mastrocola,Raffaella, AU - Chiazza,Fausto, AU - Cento,Alessia Sofia, AU - Murphy,Catherine, AU - Verta,Roberta, AU - Alves,Gustavo Ferreira, AU - Gaudioso,Giulia, AU - Fava,Francesca, AU - Yaqoob,Magdi, AU - Aragno,Manuela, AU - Tuohy,Kieran, AU - Thiemermann,Christoph, AU - Collino,Massimo, Y1 - 2020/05/13/ PY - 2020/03/13/received PY - 2020/04/20/revised PY - 2020/04/28/accepted PY - 2020/5/16/pubmed PY - 2021/7/9/medline PY - 2020/5/16/entrez KW - Baricitinib KW - High-fat-high sugar diet KW - Insulin resistance KW - JAK2-STAT2 pathway KW - Metaflammation SP - 101009 EP - 101009 JF - Molecular metabolism JO - Mol Metab VL - 39 N2 - 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. SN - 2212-8778 UR - https://www.unboundmedicine.com/medline/citation/32413585/Baricitinib_counteracts_metaflammation_thus_protecting_against_diet_induced_metabolic_abnormalities_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2212-8778(20)30083-1 DB - PRIME DP - Unbound Medicine ER -