Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice.

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: 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
• Journal: Molecular metabolism (Mol Metab) Vol. 39 Pg. 101009 (09 2020) ISSN: 2212-8778 [Electronic] Germany
• PMID: 32413585 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Azetidines
• Biomarkers
• Insulin
• Janus Kinase Inhibitors
• Purines
• Pyrazoles
• STAT Transcription Factors
• Sulfonamides
• Jak2 protein, mouse
• Janus Kinase 2
• baricitinib
• Glucose

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Azetidines (pharmacology)
• Biomarkers
• Diet, High-Fat (adverse effects)
• Disease Models, Animal
• Energy Metabolism (drug effects)
• Gastrointestinal Microbiome (drug effects)
• Glucose (metabolism)
• Immunohistochemistry
• Inflammation (drug therapy, etiology, metabolism)
• Insulin (metabolism)
• Janus Kinase 2 (metabolism)
• Janus Kinase Inhibitors (pharmacology)
• Male
• Metabolic Diseases (diagnosis, drug therapy, etiology, metabolism)
• Mice
• Muscle, Skeletal (diagnostic imaging, drug effects, metabolism)
• Purines (pharmacology)
• Pyrazoles (pharmacology)
• STAT Transcription Factors (metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)