Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation.
Metformin ameliorates experimental-obesity-associated autoimmune arthritis by inducing FGF21 expression and brown adipocyte differentiation.
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DOI：
10.1038/emm.2017.245
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发表时间：
2018-01-26
影响因子：
12.8
通讯作者：
Cho ML
中科院分区：
文献类型：
--
作者：
Kim EK;Lee SH;Lee SY;Kim JK;Jhun JY;Na HS;Kim SY;Choi JY;Yang CW;Park SH;Cho ML
类风湿关节炎(RA)是一种涉及过度炎症的全身性自身免疫性疾病。最近，与代谢紊乱相关的类风湿关节炎被发现对类风湿关节炎药物无反应。据报道，二甲双胍对类风湿关节炎和肥胖症有治疗作用。本研究的目的是在肥胖性胶原诱导性关节炎(CIA)的实验模型上研究二甲双胍的治疗作用及其可能的机制。在13周的时间里，每天给患有CIA的小鼠服用二甲双胍，这些小鼠喂食了高脂饮食。二甲双胍通过减少自身抗体的表达和关节炎症来改善肥胖小鼠的CIA发展。此外，二甲双胍降低了pSTAT3和pmTOR的表达水平，并对肥胖CIA小鼠的代谢谱起到了较小的正常化作用。此外，二甲双胍还增加了PAMPK和FGF21的产量。二甲双胍还可以诱导棕色脂肪组织(BAT)的分化，从而在体内外导致辅助性T细胞(Th)17和调节性T细胞(Treg)之间的相互平衡。这些结果表明，二甲双胍可以抑制肥胖小鼠CIA的发展，并通过诱导BAT分化来减少代谢功能障碍。因此，二甲双胍可能成为治疗无反应性类风湿关节炎的候选药物。
Rheumatoid arthritis (RA) is a systemic autoimmune disease involving excessive inflammation. Recently, RA associated with a metabolic disorder was revealed to be non-responsive to RA medications. Metformin has been reported to have a therapeutic effect on RA and obesity. The aim of this investigation was to study the therapeutic effect and the underlying mechanism of metformin's action in an experimental model of collagen-induced arthritis (CIA) associated with obesity. Metformin was administered daily for 13 weeks to mice with CIA that had been fed a high-fat diet. Metformin ameliorated the development of CIA in obese mice by reducing autoantibody expression and joint inflammation. Furthermore, metformin decreased the expression levels of pSTAT3 and pmTOR and had a small normalizing effect on the metabolic profile of obese CIA mice. In addition, metformin increased the production of pAMPK and FGF21. Metformin also induced the differentiation of brown adipose tissue (BAT), which led to a reciprocal balance between T helper (Th) 17 and regulatory T (Treg) cells in vitro and in vivo. These results suggest that metformin can dampen the development of CIA in obese mice and reduce metabolic dysfunction by inducing BAT differentiation. Thus, metformin could be a therapeutic candidate for non-responsive RA.
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