MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease.
MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic disease.
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DOI：
10.1161/circresaha.109.199166
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发表时间：
2009-07-02
影响因子：
20.1
通讯作者：
Kleemann R
中科院分区：
文献类型：
--
作者：
Verschuren L;Kooistra T;Bernhagen J;Voshol PJ;Ouwens DM;van Erk M;de Vries-van der Weij J;Leng L;van Bockel JH;van Dijk KW;Fingerle-Rowson G;Bucala R;Kleemann R
白色脂肪组织(WAT)的慢性炎症与肥胖、胰岛素抵抗(IR)和2型糖尿病(T2D)的发生呈正相关。促炎症细胞因子巨噬细胞移动抑制因子(MIF)是炎症级联反应的重要上游成分。本研究旨在探讨低密度脂蛋白受体缺陷(LDLR-−/−)小鼠的肥胖、胰岛素抵抗、糖耐量减低和动脉粥样硬化等疾病的发生是否需要微血管生成因子。低密度脂蛋白受体−/−小鼠在15周内出现IR和糖耐量异常，而Mif−/−Ldlr−/−仔鼠受到保护。MIF缺乏症不影响肥胖和脂质风险因素，但特别减少WAT和肝脏的炎症，反映在基线和炎症条件下较低的血浆SAA和纤维蛋白原水平。相反，MIF刺激体内人类C反应蛋白的表达，人C反应蛋白是IR和心血管疾病的炎症标志物和危险因素。在WAT中，MIF缺乏降低了核c-jun水平，改善了胰岛素敏感性；MIF缺乏也减少了WAT中巨噬细胞的聚集，并钝化了调节巨噬细胞渗透的两种蛋白(ICAM-1，CD44)的表达。在主动脉中观察到了与WAT相似的机制，MIF的缺乏降低了单核细胞黏附、巨噬细胞病变含量和动脉粥样硬化病变的大小。这些数据强调了慢性炎症在IR和动脉粥样硬化发展中的生理重要性，并表明MIF是减少代谢和心血管疾病的炎症成分的潜在治疗靶点。
Chronic inflammation in white adipose tissue (WAT) is positively associated with obesity, insulin resistance (IR) and the development of type-2 diabetes (T2D). The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) is an essential, upstream component of the inflammatory cascade. This study examines whether MIF is required for the development of obesity, IR, glucose intolerance and atherosclerosis in the LDL-receptor-deficient (Ldlr−/−) mouse model of disease. Ldlr−/−-mice develop IR and glucose intolerance within 15-w while Mif−/−Ldlr−/− littermates are protected. MIF-deficiency does not affect obesity and lipid risk factors but specifically reduces inflammation in WAT and liver, as reflected by lower plasma SAA and fibrinogen levels at baseline and under inflammatory conditions. Conversely, MIF stimulates the in vivo expression of human-CRP, an inflammation marker and risk factor of IR and cardiovascular-disease. In WAT, MIF-deficiency reduces nuclear c-Jun levels and improves insulin sensitivity; MIF-deficiency also reduces macrophage accumulation in WAT and blunts the expression of two proteins that regulate macrophage infiltration (ICAM-1, CD44). Mechanistic parallels to WAT were observed in aorta, where the absence of MIF reduces monocyte adhesion, macrophage lesion content and atherosclerotic lesion size. These data highlight the physiological importance of chronic inflammation in development of IR and atherosclerosis, and suggest that MIF is a potential therapeutic target for reducing the inflammatory component of metabolic and cardiovascular disorders.