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Published on: November 16, 2011
Mitogen-activated protein kinase-activated protein kinase 2 deficiency reduces insulin sensitivity in high-fat
Jan Freark de Boer1, Arne Dikkers1, Angelika Jurdzinski1
1Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Abstract:
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.
Insights
Mitogen-activated protein kinase-activated protein kinase 2 (MK2) deficiency worsens insulin resistance and glucose intolerance in mice fed a high-fat diet. This suggests caution is needed when considering MK2 inhibitors for treating inflammatory diseases due to potential metabolic side effects.
Area of Science:
- Metabolic disease research
- Inflammation and immunology
- Molecular and cellular biology
Background:
- Adipose tissue inflammation is a key factor in insulin resistance.
- Mitogen-activated protein kinase-activated protein kinase 2 (MK2) promotes inflammation and is a therapeutic target.
- MK2 knockout (MK2-/-) mice show protection against inflammation in various models.
Purpose of the Study:
- To investigate the effect of MK2 deficiency on high-fat diet (HFD)-induced adipose tissue inflammation and insulin resistance.
- To determine if MK2 plays a role in metabolic dysfunction.
Main Methods:
- Mice lacking MK2 (MK2-/-) and wild-type (WT) controls were fed a HFD for 24 weeks.
- Evaluated body weight, liver weight, abdominal fat, plasma cholesterol, macrophage infiltration, and macrophage polarization.
- Assessed glucose and insulin tolerance, and measured glucose transporter type 4 (GLUT4) expression.
Main Results:
- No significant differences in body weight, liver weight, or abdominal fat between MK2-/- and WT mice.
- MK2-/- mice exhibited increased plasma cholesterol, M1-skewed adipose tissue macrophages, reduced glucose tolerance, and increased insulin resistance.
- Adipose tissue GLUT4 expression (mRNA and protein) was significantly reduced in MK2-/- mice.
Conclusions:
- MK2 deficiency exacerbates HFD-induced insulin resistance and glucose intolerance in mice.
- Reduced adipose tissue GLUT4 expression may contribute to the observed metabolic phenotype.
- Clinical use of MK2 inhibitors requires careful consideration of potential metabolic adverse effects.
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