Limits...
MNK1 and MNK2 mediate adverse effects of high-fat feeding in distinct ways.

Moore CE, Pickford J, Cagampang FR, Stead RL, Tian S, Zhao X, Tang X, Byrne CD, Proud CG - Sci Rep (2016)

Bottom Line: This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology.These data suggest MNK1 participates in mediating HFD-induced insulin resistance.Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.

ABSTRACT
The MAP kinase-interacting kinases (MNK1 and MNK2) are non-essential enzymes which are activated by MAP kinases. They are implicated in controlling protein synthesis. Here we show that mice in which the expression of either MNK1 or MNK2 has been knocked out (KO) are protected against adverse effects of high-fat feeding, and in distinct ways. High-fat diet (HFD)-fed MNK2-KO show less weight gain than wild-type animals, and improved glucose tolerance, better insulin sensitivity and markedly diminished adipose tissue inflammation. This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology. MNK1-KO/HFD mice show better glucose tolerance and insulin sensitivity, but gain weight and show similar adipose inflammation to WT animals. These data suggest MNK1 participates in mediating HFD-induced insulin resistance. Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.

No MeSH data available.


Related in: MedlinePlus

Effects of knocking out or inhibiting MNKs on adipocytes.(a) The average sizes of fat cells in WT and MNK2-KO mice fed chow or the HFD were analysed and quantified by image J software (WT chow n = 3, WT HFD n = 3, MNK2-KO chow n = 3, MNK2-KO HFD n = 3). Data are mean ± SEM (2-tailed, unpaired Student’s t test). **P < 0.01. (b) Right panel: undifferentiated 3T3-L1 cells were treated with the indicated concentrations of CGP57380 for 72 h. Lysates were analysed by immunoblot using the indicated antibodies, representative of 3 independent experiments. Below: Quantification of the data shown in the top panel. Data are mean ± SEM (one-way ANOVA with Tukey’s post-test) ****P < 0.0001. (c) 3T3-L1 cells were left to differentiate for 9 days in the absence or presence of 20 μM CGP57380 and cells were then stained with Oil Red O. Representative microscopic fields of view are shown, scale bars, 176 μm. Quantification of lipid incorporation by measurement of the intensity of Oil Red O staining (n = 3). Data are mean ± SEM relative to control (100%) (2-tailed, unpaired Student’s t test) **P < 0.01. (d) mRNA expression of PPARγ, C/EBPα, SREBP1c, GLUT4 and CD36 in 3T3-L1 adipocytes subjected to the differentiation program in the presence or absence 20 μM CGP57380 (n = 3). Data are mean ± SEM (one-way ANOVA with Tukey’s post-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834573&req=5

f3: Effects of knocking out or inhibiting MNKs on adipocytes.(a) The average sizes of fat cells in WT and MNK2-KO mice fed chow or the HFD were analysed and quantified by image J software (WT chow n = 3, WT HFD n = 3, MNK2-KO chow n = 3, MNK2-KO HFD n = 3). Data are mean ± SEM (2-tailed, unpaired Student’s t test). **P < 0.01. (b) Right panel: undifferentiated 3T3-L1 cells were treated with the indicated concentrations of CGP57380 for 72 h. Lysates were analysed by immunoblot using the indicated antibodies, representative of 3 independent experiments. Below: Quantification of the data shown in the top panel. Data are mean ± SEM (one-way ANOVA with Tukey’s post-test) ****P < 0.0001. (c) 3T3-L1 cells were left to differentiate for 9 days in the absence or presence of 20 μM CGP57380 and cells were then stained with Oil Red O. Representative microscopic fields of view are shown, scale bars, 176 μm. Quantification of lipid incorporation by measurement of the intensity of Oil Red O staining (n = 3). Data are mean ± SEM relative to control (100%) (2-tailed, unpaired Student’s t test) **P < 0.01. (d) mRNA expression of PPARγ, C/EBPα, SREBP1c, GLUT4 and CD36 in 3T3-L1 adipocytes subjected to the differentiation program in the presence or absence 20 μM CGP57380 (n = 3). Data are mean ± SEM (one-way ANOVA with Tukey’s post-test).

Mentions: In WT-HFD mice, adipocyte size increased substantially, as assessed by cell area (1.7 fold; Fig. 3a). Consistent with this, there was a corresponding decrease in the observed number of adipocytes seen in each field for HFD-fed WT compared to chow-fed mice. In contrast, adipocyte size in MNK2-KO/HFD mice did not increase when compared to chow-fed controls (Fig. 3a), suggesting there may be a defect in adipocyte lipid storage when these animals are fed the HFD. Interestingly, adipocyte size was larger in MNK2/chow animals than WT controls, suggesting that a possible deficit in adipogenesis in MNK2-KO mice, resulting in fewer adipocytes, each becoming bigger on the chow diet. The lack of increase in adipocyte size in MNK2-KO/HFD mice likely contributes to their blunted weight gain.


MNK1 and MNK2 mediate adverse effects of high-fat feeding in distinct ways.

Moore CE, Pickford J, Cagampang FR, Stead RL, Tian S, Zhao X, Tang X, Byrne CD, Proud CG - Sci Rep (2016)

Effects of knocking out or inhibiting MNKs on adipocytes.(a) The average sizes of fat cells in WT and MNK2-KO mice fed chow or the HFD were analysed and quantified by image J software (WT chow n = 3, WT HFD n = 3, MNK2-KO chow n = 3, MNK2-KO HFD n = 3). Data are mean ± SEM (2-tailed, unpaired Student’s t test). **P < 0.01. (b) Right panel: undifferentiated 3T3-L1 cells were treated with the indicated concentrations of CGP57380 for 72 h. Lysates were analysed by immunoblot using the indicated antibodies, representative of 3 independent experiments. Below: Quantification of the data shown in the top panel. Data are mean ± SEM (one-way ANOVA with Tukey’s post-test) ****P < 0.0001. (c) 3T3-L1 cells were left to differentiate for 9 days in the absence or presence of 20 μM CGP57380 and cells were then stained with Oil Red O. Representative microscopic fields of view are shown, scale bars, 176 μm. Quantification of lipid incorporation by measurement of the intensity of Oil Red O staining (n = 3). Data are mean ± SEM relative to control (100%) (2-tailed, unpaired Student’s t test) **P < 0.01. (d) mRNA expression of PPARγ, C/EBPα, SREBP1c, GLUT4 and CD36 in 3T3-L1 adipocytes subjected to the differentiation program in the presence or absence 20 μM CGP57380 (n = 3). Data are mean ± SEM (one-way ANOVA with Tukey’s post-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834573&req=5

f3: Effects of knocking out or inhibiting MNKs on adipocytes.(a) The average sizes of fat cells in WT and MNK2-KO mice fed chow or the HFD were analysed and quantified by image J software (WT chow n = 3, WT HFD n = 3, MNK2-KO chow n = 3, MNK2-KO HFD n = 3). Data are mean ± SEM (2-tailed, unpaired Student’s t test). **P < 0.01. (b) Right panel: undifferentiated 3T3-L1 cells were treated with the indicated concentrations of CGP57380 for 72 h. Lysates were analysed by immunoblot using the indicated antibodies, representative of 3 independent experiments. Below: Quantification of the data shown in the top panel. Data are mean ± SEM (one-way ANOVA with Tukey’s post-test) ****P < 0.0001. (c) 3T3-L1 cells were left to differentiate for 9 days in the absence or presence of 20 μM CGP57380 and cells were then stained with Oil Red O. Representative microscopic fields of view are shown, scale bars, 176 μm. Quantification of lipid incorporation by measurement of the intensity of Oil Red O staining (n = 3). Data are mean ± SEM relative to control (100%) (2-tailed, unpaired Student’s t test) **P < 0.01. (d) mRNA expression of PPARγ, C/EBPα, SREBP1c, GLUT4 and CD36 in 3T3-L1 adipocytes subjected to the differentiation program in the presence or absence 20 μM CGP57380 (n = 3). Data are mean ± SEM (one-way ANOVA with Tukey’s post-test).
Mentions: In WT-HFD mice, adipocyte size increased substantially, as assessed by cell area (1.7 fold; Fig. 3a). Consistent with this, there was a corresponding decrease in the observed number of adipocytes seen in each field for HFD-fed WT compared to chow-fed mice. In contrast, adipocyte size in MNK2-KO/HFD mice did not increase when compared to chow-fed controls (Fig. 3a), suggesting there may be a defect in adipocyte lipid storage when these animals are fed the HFD. Interestingly, adipocyte size was larger in MNK2/chow animals than WT controls, suggesting that a possible deficit in adipogenesis in MNK2-KO mice, resulting in fewer adipocytes, each becoming bigger on the chow diet. The lack of increase in adipocyte size in MNK2-KO/HFD mice likely contributes to their blunted weight gain.

Bottom Line: This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology.These data suggest MNK1 participates in mediating HFD-induced insulin resistance.Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.

View Article: PubMed Central - PubMed

Affiliation: Centre for Biological Sciences, University of Southampton, Southampton, SO17 1BJ, United Kingdom.

ABSTRACT
The MAP kinase-interacting kinases (MNK1 and MNK2) are non-essential enzymes which are activated by MAP kinases. They are implicated in controlling protein synthesis. Here we show that mice in which the expression of either MNK1 or MNK2 has been knocked out (KO) are protected against adverse effects of high-fat feeding, and in distinct ways. High-fat diet (HFD)-fed MNK2-KO show less weight gain than wild-type animals, and improved glucose tolerance, better insulin sensitivity and markedly diminished adipose tissue inflammation. This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology. MNK1-KO/HFD mice show better glucose tolerance and insulin sensitivity, but gain weight and show similar adipose inflammation to WT animals. These data suggest MNK1 participates in mediating HFD-induced insulin resistance. Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.

No MeSH data available.


Related in: MedlinePlus