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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 expression of selected genes in liver of WT and MNK2-KO mice.(a,b) Total RNA was isolated from liver tissue from chow-fed and HFD-fed WT and MNK2-KO mice. The relative expression of NRF2 and its downstream target heme oxygenase 1 (HO1) was measured by means of qPCR (n = 4). Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD) *P < 0.05. (c–f) The relative expression of genes involved in de novo lipogenesis (SREBP1c, FAS, ACC1) and β-oxidation (CPT1A) in the liver from chow-fed and HFD-fed WT and MNK2-KO mice were measured by qPCR (n = 4). Data are mean ± SEM relative to WT chow (2-tailed, unpaired Student’s t test) *P < 0.05, **P < 0.01.
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f8: Analysis of expression of selected genes in liver of WT and MNK2-KO mice.(a,b) Total RNA was isolated from liver tissue from chow-fed and HFD-fed WT and MNK2-KO mice. The relative expression of NRF2 and its downstream target heme oxygenase 1 (HO1) was measured by means of qPCR (n = 4). Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD) *P < 0.05. (c–f) The relative expression of genes involved in de novo lipogenesis (SREBP1c, FAS, ACC1) and β-oxidation (CPT1A) in the liver from chow-fed and HFD-fed WT and MNK2-KO mice were measured by qPCR (n = 4). Data are mean ± SEM relative to WT chow (2-tailed, unpaired Student’s t test) *P < 0.05, **P < 0.01.

Mentions: Nuclear factor erythroid 2-related factor 2 (Nrf2) is important in protection against oxidative stress26, which can arise from extensive fatty acid oxidation27. Nrf2 is reported to protect against development of the metabolic syndrome (reviewed26) and steatosis28. Given that MNK2-KO mice show protection against indices of metabolic syndrome, we analysed the expression of Nrf2 in livers of WT and MNK2-KO mice. Levels were similar in mice fed a chow diet. Nrf2 mRNA levels increased markedly in MNK2-KO mice fed a HFD, but not in the corresponding control animals (Fig. 8a). To confirm increased Nrf2 function, we tested expression of haem oxygenase-1 (HO-1; an Nrf2 target gene), which showed a similar pattern to Nrf2 (Fig. 8b). Nrf2 can be transcriptionally controlled by PPARα29; however, we saw no differences in PPARα levels in liver of MNK2-KO or WT mice on the HFD (Supplemental Fig. 5c).


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 expression of selected genes in liver of WT and MNK2-KO mice.(a,b) Total RNA was isolated from liver tissue from chow-fed and HFD-fed WT and MNK2-KO mice. The relative expression of NRF2 and its downstream target heme oxygenase 1 (HO1) was measured by means of qPCR (n = 4). Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD) *P < 0.05. (c–f) The relative expression of genes involved in de novo lipogenesis (SREBP1c, FAS, ACC1) and β-oxidation (CPT1A) in the liver from chow-fed and HFD-fed WT and MNK2-KO mice were measured by qPCR (n = 4). Data are mean ± SEM relative to WT chow (2-tailed, unpaired Student’s t test) *P < 0.05, **P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f8: Analysis of expression of selected genes in liver of WT and MNK2-KO mice.(a,b) Total RNA was isolated from liver tissue from chow-fed and HFD-fed WT and MNK2-KO mice. The relative expression of NRF2 and its downstream target heme oxygenase 1 (HO1) was measured by means of qPCR (n = 4). Data are mean ± SEM (2-tailed, unpaired Student’s t test comparing WT/HFD vs MNK2-KO/HFD) *P < 0.05. (c–f) The relative expression of genes involved in de novo lipogenesis (SREBP1c, FAS, ACC1) and β-oxidation (CPT1A) in the liver from chow-fed and HFD-fed WT and MNK2-KO mice were measured by qPCR (n = 4). Data are mean ± SEM relative to WT chow (2-tailed, unpaired Student’s t test) *P < 0.05, **P < 0.01.
Mentions: Nuclear factor erythroid 2-related factor 2 (Nrf2) is important in protection against oxidative stress26, which can arise from extensive fatty acid oxidation27. Nrf2 is reported to protect against development of the metabolic syndrome (reviewed26) and steatosis28. Given that MNK2-KO mice show protection against indices of metabolic syndrome, we analysed the expression of Nrf2 in livers of WT and MNK2-KO mice. Levels were similar in mice fed a chow diet. Nrf2 mRNA levels increased markedly in MNK2-KO mice fed a HFD, but not in the corresponding control animals (Fig. 8a). To confirm increased Nrf2 function, we tested expression of haem oxygenase-1 (HO-1; an Nrf2 target gene), which showed a similar pattern to Nrf2 (Fig. 8b). Nrf2 can be transcriptionally controlled by PPARα29; however, we saw no differences in PPARα levels in liver of MNK2-KO or WT mice on the HFD (Supplemental Fig. 5c).

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