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Exploring the functions of MAPK-interacting kinases (MNKs) in metabolic disease

Explore the functions of MAPK-interacting kinases (MNKs) in metabolic disease at the South Australian Health and Medical Research Institute.

MNKs play a key role in promoting adipocyte differentiation and this will be explored using the 3T3-L1 system

Figure. The MNKs play a key role in promoting adipocyte differentiation and this will be explored using the 3T3-L1 system.

Metabolic disease: In Australia and many other countries, the prevalence of overweight and obesity have increased significantly over the past two decades. The most recent population data indicate almost two-thirds of Australian adults are overweight or obese. 

Being overweight or obese increases the risk of developing long-term comorbidities including cardiovascular disease, hypertension and type-2 diabetes. These diseases present an enormous burden to patients, their carers, health systems, and communities. 

There is therefore an urgent need to understand the mechanisms underlying obesity and weight gain and to explore novel therapeutic strategies to tackle the obesity ‘epidemic’. 

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are a family of kinases activated by signalling through MAPK (ERK and p38) pathways. The best-studied and only validated in vivo substrate of the MNKs is eukaryotic initiation factor 4E (eIF4E), which binds the 5’-m7G cap structure of eukaryotic mRNAs to facilitate the recruitment of ribosomes and their subsequent scanning to initiate mRNA translation. eIF4E phosphorylation is not critical for general mRNA translation and its biological significance is yet to be fully resolved (Ueda et al., 2004). 

It is suggested however, that phosphorylation may cause the release of eIF4E from the initiation complex, enabling it to initiate another round of mRNA translation and/or to recruit additional mRNAs into active polyribosomes. The phosphorylation of eIF4E may also be important for regulating the translation of specific mRNAs in response to certain stimuli. 

MNKs are novel potential targets in metabolic disease: Recently, the MNKs were identified as a novel potential therapeutic target for managing obesity and improving metabolic health (Moore et al., 2016). Eliminating MNK activity protects animals fed a high-fat diet (HFD) from weight gain, adipose tissue (AT) inflammation and the onset of glucose intolerance, which leads to type-2 diabetes. We hypothesise that MNKs play a key role in the biology of AT and muscle. 

Adipose tissue is a dynamic, hormone-responsive tissue that adapts to energy requirements, storing excess nutrients in times of energy abundance (fed state) and releasing them in times of energy deprivation (fasting) to maintain systemic energy homeostasis. 

Our data show that MNKs play a key role in the differentiation of fat cells (adipocytes) by regulating the induction of genes that are key players in adipogenesis. MNKs likely control the expression and/or function of the transcription factors that drive adipogenesis. This may explain why MNK knock-out mice gain less weight on a HFD.

The major tissue responsible for insulin-stimulated glucose uptake from the blood is skeletal muscle. Insulin stimulates glucose uptake by eliciting the mobilisation of the glucose transporter 4 (GLUT4) from intracellular vesicular compartments to the cell membrane. 

A key player here is protein kinase B (PKB, also called Akt) which is activated by insulin and controls GLUT4 localisation. Insulin resistance is a major characteristic of type-2 diabetes whereby the capacity of insulin to increase glucose uptake is significantly reduced. Our data indicate that MNKs may regulate the ability of insulin to switch on PKB and glucose transport.

This may explain why HFD-fed MNK-KO mice retain better glucose tolerance that WT animals.

Cell systems to be used in this project

We have shown that knock out mice lacking MNKs fed a high fat-diet gain less weight and display improved glucose metabolism such as lower circulating blood glucose levels and greater insulin sensitivity compared to WT mice. We hypothesise that the MNKs play a role adipose biology and insulin-regulated metabolism in skeletal muscle. 

For this project, the murine 3T3-L1 pre-adipocyte and C2C12 murine myoblast (muscle) lines will be the primary models of investigation. The 3T3-L1 model is the ‘gold-standard’ for studying adipocyte differentiation and biology, while C2C12 myoblasts can be differentiated into contracting myotubes upon serum depletion and express proteins characteristic of functionally mature muscle cells. 

Professor Chris Proud

Supervisor

Professor Christopher G Proud

Research area: Cell signalling and gene regulation; Nutrition and metabolism, South Australian Health and Medical Research Institute

Recommended honours enrolment: Honours in Molecular and Biomedical Science

Tagged in Honours projects - Molecular and biomedical science, Honours projects - Chris Proud, Honours projects - Molecular and biomedical science: Biochemistry