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

Abstract Objective Recent evidence suggests a substantial pathogenic role for the Janus kinase (Jak)/signal transducer and activator of transcription (Stat) pathway in the development of the low grade chronic inflammatory response, known as “metaflammation”, which contributes to obesity and type 2 diabetes. Here we investigated the effects of the Jak1/2 inhibitor baricitinib, recently approved for the treatment of rheumatoid arthritis, in a murine model of high-fat diet. Methods Male C57BL/6 mice were fed with a control normal diet (ND) or a high fat diet (HD) for 22 weeks. Sub-group of HD-fed mice treated with baricitinib (10 mg/kg die, p.o.) for the last 16 weeks. 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 gut, but restored insulin signaling in 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. Additionally, we demonstrated that restored tissue levels of Jak2/Stat2 activity were associated with significant reduction of cytokines 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 potential for the EMA- and FDA-approved Jak inhibitors to be repurposed for the treatment of type 2 diabetes and/or its complications.