University of Groningen Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Deficiency Reduces Insulin Sensitivity in High-Fat Diet-Fed Mice

Adipose tissue inflammation is considered an important contributor to insulin resistance. Mitogen-activated protein kinaseactivated 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, Tnfa 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. Citation: de Boer JF, Dikkers A, Jurdzinski A, von Felden J, Gaestel M, et al. (2014) Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Deficiency Reduces Insulin Sensitivity in High-Fat Diet-Fed Mice. PLoS ONE 9(9): e106300. doi:10.1371/journal.pone. 0106300 Editor: Makoto Kanzaki, Tohoku University, Japan Received May 22, 2014; Accepted August 4, 2014; Published September 18, 2014 Copyright: 2014 de Boer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This study was funded by the Groningen Expert Center for Kids with Obesity (GECKO, to U.J.F.T.), by a grant from the Netherlands Organization for Scientific Research (VIDI Grant 917-56-358, to UJFT) and the Deutsche Forschungsgemeinschaft (SFB 566 B12 to M.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: u_tietge@yahoo.com