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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

Analysis of signaling pathways in tissues from MNK-KO mice.(a) Total protein was isolated from gonadal adipose tissue from chow-fed and HFD-fed WT, MNK1-KO and MNK2-KO mice. Lysates were analysed by immunoblot using the indicated antibodies; representative of 3 independent samples. Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (b,c) Mice were fasted overnight before receiving an intraperitoneal injection of 0.75 U/kg insulin. Animals were sacrificed 30 min later, and tissues were collected for immunoblot analysis using the indicated antibodies. Representative immunoblot of WT, MNK1-KO and MNK2-KO adipose tissue (b) and skeletal muscle (c) are shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (d) Upper panel as in (a) lysates were analysed by immunoblot to assess GLUT4 levels. Lower panel: quantification of data from multiple experiments as in (a) expressed as GLUT4 normalized to actin. Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD or MNK1-KO/HFD) *P < 0.05. (e) as in (a,e) Upper panel: representative immunoblot of WT, MNK1-KO and MNK2-KO skeletal muscle is shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). Lower panel: quantification of data from multiple experiments expressed as GLUT4 normalized to eIF4E.
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f5: Analysis of signaling pathways in tissues from MNK-KO mice.(a) Total protein was isolated from gonadal adipose tissue from chow-fed and HFD-fed WT, MNK1-KO and MNK2-KO mice. Lysates were analysed by immunoblot using the indicated antibodies; representative of 3 independent samples. Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (b,c) Mice were fasted overnight before receiving an intraperitoneal injection of 0.75 U/kg insulin. Animals were sacrificed 30 min later, and tissues were collected for immunoblot analysis using the indicated antibodies. Representative immunoblot of WT, MNK1-KO and MNK2-KO adipose tissue (b) and skeletal muscle (c) are shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (d) Upper panel as in (a) lysates were analysed by immunoblot to assess GLUT4 levels. Lower panel: quantification of data from multiple experiments as in (a) expressed as GLUT4 normalized to actin. Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD or MNK1-KO/HFD) *P < 0.05. (e) as in (a,e) Upper panel: representative immunoblot of WT, MNK1-KO and MNK2-KO skeletal muscle is shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). Lower panel: quantification of data from multiple experiments expressed as GLUT4 normalized to eIF4E.

Mentions: To assess the relative contributions of MNK1/2 to overall MNK activity in adipose tissue, we examined phosphorylation of eIF4E, their common substrate5. The HFD caused a small increase in phosphorylated (P)-eIF4E (Fig. 5a) in WT mice but this did not reach statistical significance. MNK2-KO mice showed substantially lower P-eIF4E under both dietary conditions. MNK1-KO mice showed no change in P-eIF4E on the chow diet and the HFD caused only an insignificant decrease in P-eIF4E. This demonstrates that MNK2 is the major/most active MNK isoform in adipose tissue.


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)

Analysis of signaling pathways in tissues from MNK-KO mice.(a) Total protein was isolated from gonadal adipose tissue from chow-fed and HFD-fed WT, MNK1-KO and MNK2-KO mice. Lysates were analysed by immunoblot using the indicated antibodies; representative of 3 independent samples. Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (b,c) Mice were fasted overnight before receiving an intraperitoneal injection of 0.75 U/kg insulin. Animals were sacrificed 30 min later, and tissues were collected for immunoblot analysis using the indicated antibodies. Representative immunoblot of WT, MNK1-KO and MNK2-KO adipose tissue (b) and skeletal muscle (c) are shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (d) Upper panel as in (a) lysates were analysed by immunoblot to assess GLUT4 levels. Lower panel: quantification of data from multiple experiments as in (a) expressed as GLUT4 normalized to actin. Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD or MNK1-KO/HFD) *P < 0.05. (e) as in (a,e) Upper panel: representative immunoblot of WT, MNK1-KO and MNK2-KO skeletal muscle is shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). Lower panel: quantification of data from multiple experiments expressed as GLUT4 normalized to eIF4E.
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f5: Analysis of signaling pathways in tissues from MNK-KO mice.(a) Total protein was isolated from gonadal adipose tissue from chow-fed and HFD-fed WT, MNK1-KO and MNK2-KO mice. Lysates were analysed by immunoblot using the indicated antibodies; representative of 3 independent samples. Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (b,c) Mice were fasted overnight before receiving an intraperitoneal injection of 0.75 U/kg insulin. Animals were sacrificed 30 min later, and tissues were collected for immunoblot analysis using the indicated antibodies. Representative immunoblot of WT, MNK1-KO and MNK2-KO adipose tissue (b) and skeletal muscle (c) are shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). (d) Upper panel as in (a) lysates were analysed by immunoblot to assess GLUT4 levels. Lower panel: quantification of data from multiple experiments as in (a) expressed as GLUT4 normalized to actin. Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD or MNK1-KO/HFD) *P < 0.05. (e) as in (a,e) Upper panel: representative immunoblot of WT, MNK1-KO and MNK2-KO skeletal muscle is shown (n = 3). Below: quantification of the data shown in the top panel. Data are mean ± SEM, (n = 3). Lower panel: quantification of data from multiple experiments expressed as GLUT4 normalized to eIF4E.
Mentions: To assess the relative contributions of MNK1/2 to overall MNK activity in adipose tissue, we examined phosphorylation of eIF4E, their common substrate5. The HFD caused a small increase in phosphorylated (P)-eIF4E (Fig. 5a) in WT mice but this did not reach statistical significance. MNK2-KO mice showed substantially lower P-eIF4E under both dietary conditions. MNK1-KO mice showed no change in P-eIF4E on the chow diet and the HFD caused only an insignificant decrease in P-eIF4E. This demonstrates that MNK2 is the major/most active MNK isoform in adipose tissue.

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