Mitogen-activated protein kinase-activated protein kinase 2 deficiency reduces insulin sensitivity in high-fat diet-fed mice
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Mitogen-activated protein kinase-activated protein kinase 2 deficiency reduces insulin sensitivity in high-fat diet-fed mice. / de Boer, Jan Freark; Dikkers, Arne; Jurdzinski, Angelika; von Felden, Johann; Gaestel, Matthias; Bavendiek, Udo; Tietge, Uwe J F.
In: PLOS ONE, Vol. 9, No. 9, 2014, p. e106300.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Mitogen-activated protein kinase-activated protein kinase 2 deficiency reduces insulin sensitivity in high-fat diet-fed mice
AU - de Boer, Jan Freark
AU - Dikkers, Arne
AU - Jurdzinski, Angelika
AU - von Felden, Johann
AU - Gaestel, Matthias
AU - Bavendiek, Udo
AU - Tietge, Uwe J F
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Abdominal Fat
KW - Adipose Tissue
KW - Animals
KW - Chemokine CCL2
KW - Cholesterol
KW - Diet, High-Fat
KW - Dyslipidemias
KW - Glucose Tolerance Test
KW - Glucose Transporter Type 4
KW - Inflammation
KW - Insulin Resistance
KW - Interleukin-6
KW - Intracellular Signaling Peptides and Proteins
KW - Liver
KW - Macrophages
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Protein-Serine-Threonine Kinases
KW - RNA, Messenger
KW - Triglycerides
KW - Tumor Necrosis Factor-alpha
KW - p38 Mitogen-Activated Protein Kinases
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1371/journal.pone.0106300
DO - 10.1371/journal.pone.0106300
M3 - SCORING: Journal article
C2 - 25233471
VL - 9
SP - e106300
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 9
ER -