de Boer Jan Freark, Dikkers Arne, Jurdzinski Angelika, von Felden Johann, Gaestel Matthias, Bavendiek Udo, Tietge Uwe J F
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Clinic of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
PLoS One. 2014 Sep 18;9(9):e106300. doi: 10.1371/journal.pone.0106300. eCollection 2014.
Adipose tissue inflammation is considered an important contributor to insulin resistance. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a major downstream target of p38 MAPK and enhances inflammatory processes. In line with the role of MK2 as contributor to inflammation, MK2-/- mice are protected against inflammation in different disease models. Therefore, MK2 is considered an attractive therapeutic target for the treatment of chronic inflammatory diseases. This study tested the impact of MK2-deficiency on high-fat diet (HFD)-induced adipose tissue inflammation and insulin resistance. After feeding MK2-/- and WT control mice a HFD (60% energy from fat) for 24 weeks, body weight was not different between groups. Also, liver weight and the amount of abdominal fat remained unchanged. However, in MK2-/- mice plasma cholesterol levels were significantly increased. Surprisingly, macrophage infiltration in adipose tissue was not altered. However, adipose tissue macrophages were more skewed to the inflammatory M1 phenotype in MK2-/- mice. This differerence in macrophage polarization did however not translate in significantly altered expression levels of Mcp-1, Tnfα and Il6. Glucose and insulin tolerance tests demonstrated that MK2-/- mice had a significantly reduced glucose tolerance and increased insulin resistance. Noteworthy, the expression of the insulin-responsive glucose transporter type 4 (GLUT4) in adipose tissue of MK2-/- mice was reduced by 55% (p<0.05) and 33% (p<0.05) on the mRNA and protein level, respectively, compared to WT mice. In conclusion, HFD-fed MK2-/- display decreased glucose tolerance and increased insulin resistance compared to WT controls. Decreased adipose tissue expression of GLUT4 might contribute to this phenotype. The data obtained in this study indicate that clinical use of MK2 inhibitors has to be evaluated with caution, taking potential metabolic adverse effects into account.
脂肪组织炎症被认为是胰岛素抵抗的一个重要促成因素。丝裂原活化蛋白激酶激活的蛋白激酶2（MK2）是p38丝裂原活化蛋白激酶的主要下游靶点，并增强炎症过程。与MK2作为炎症促成因素的作用一致，在不同疾病模型中，MK2基因敲除小鼠对炎症具有抵抗力。因此，MK2被认为是治疗慢性炎症性疾病的一个有吸引力的治疗靶点。本研究测试了MK2缺陷对高脂饮食（HFD）诱导的脂肪组织炎症和胰岛素抵抗的影响。给MK2基因敲除小鼠和野生型对照小鼠喂食高脂饮食（脂肪提供60%的能量）24周后，两组小鼠的体重没有差异。此外，肝脏重量和腹部脂肪量保持不变。然而，MK2基因敲除小鼠的血浆胆固醇水平显著升高。令人惊讶的是，脂肪组织中的巨噬细胞浸润没有改变。然而，在MK2基因敲除小鼠中，脂肪组织巨噬细胞更倾向于促炎性M1表型。然而，巨噬细胞极化的这种差异并没有转化为Mcp-1、Tnfα和Il6表达水平的显著改变。葡萄糖和胰岛素耐量试验表明，MK2基因敲除小鼠的葡萄糖耐量显著降低，胰岛素抵抗增加。值得注意的是，与野生型小鼠相比，MK2基因敲除小鼠脂肪组织中胰岛素反应性葡萄糖转运蛋白4（GLUT4）的表达在mRNA水平和蛋白水平分别降低了55%（p<0.05）和33%（p<0.05）。总之，与野生型对照相比，喂食高脂饮食的MK2基因敲除小鼠表现出葡萄糖耐量降低和胰岛素抵抗增加。脂肪组织中GLUT4表达降低可能导致这种表型。本研究获得的数据表明，在考虑潜在代谢不良反应的情况下，必须谨慎评估MK2抑制剂的临床应用。
