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.

中文翻译：

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Baricitinib可以抵消炎症，从而防止饮食引起的小鼠代谢异常。

目的

最近的证据表明，Janus激酶（JAK）/信号转导子和转录激活子（STAT）通路在低度慢性炎症反应（称为“ metaflammation”）的发生中起着重要的致病作用，这种现象会导致肥胖和2型糖尿病。在这项研究中，我们在鼠高脂高糖饮食模型中研究了JAK1 / 2抑制剂baricitinib（最近被批准用于治疗类风湿性关节炎）的作用。

方法

给雄性C57BL / 6小鼠喂食正常对照饮食（ND）或高脂高糖饮食（HD）22周。在最后16周内，用Baricitinib（10 mg / kg死，口服）治疗HD喂养小鼠的一个亚组（HD + Bar）。

结果

高清晰度喂养导致肥胖，胰岛素抵抗，高胆固醇血症和肠道微生物组成改变。长期使用baricitinib可显着减少代谢异常。用Baricitinib治疗HD小鼠并未改变饮食引起的肠道改变，但恢复了肝脏和骨骼肌中的胰岛素信号传导，从而改善了饮食引起的肌脂代谢，肾小球膜扩张和相关蛋白尿。骨骼肌和肾脏保护作用是由于Baricitinib抑制了局部JAK2-STAT2途径。我们还证明，JAK2-STAT2活性的恢复组织水平与血液中细胞因子水平的显着降低有关。

结论

总而言之，我们的数据表明，JAK2-STAT2途径可能代表了与饮食相关的代谢紊乱的新型治疗方法，可能被EMA和FDA批准的JAK抑制剂重新用于治疗2型糖尿病和糖尿病。 /或其并发症。