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.

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Authors+Show Affiliations

Collotta D
Department of Drug Science and Technology, University of Turin, Turin, Italy.
Hull W
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.
Mastrocola R
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Chiazza F
Department of Drug Science and Technology, University of Turin, Turin, Italy.
Cento AS
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Murphy C
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.
Verta R
Department of Drug Science and Technology, University of Turin, Turin, Italy.
Alves GF
Department of Drug Science and Technology, University of Turin, Turin, Italy.
Gaudioso G
Edmund Mach Foundation, San Michele all'Adige, Italy.
Fava F
Edmund Mach Foundation, San Michele all'Adige, Italy.
Yaqoob M
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.
Aragno M
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Tuohy K
Edmund Mach Foundation, San Michele all'Adige, Italy.
Thiemermann C
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.
Collino M
Department of Drug Science and Technology, University of Turin, Turin, Italy. Electronic address: massimo.collino@unito.it.

MeSH

AnimalsAnti-Inflammatory AgentsAzetidinesBiomarkersDiet, High-FatDisease Models, AnimalEnergy MetabolismGastrointestinal MicrobiomeGlucoseImmunohistochemistryInflammationInsulinJanus Kinase 2Janus Kinase InhibitorsMaleMetabolic DiseasesMiceMuscle, SkeletalPurinesPyrazolesSTAT Transcription FactorsSignal TransductionSulfonamides

Pub Type(s)

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

Language

eng

PubMed ID

32413585