Oral Presentation ANZOS-OSSANZ-AOCO Joint Annual Scientific Meeting 2017

The MNK protein kinases mediate adverse responses to high fat feeding (#94)

Christopher Proud 1
  1. South Australian Health and Medical Research Institute, Adelaide, SA, Australia

Obesity and its consequences, including glucose intolerance and type-2 diabetes, pose serious and costly challenges for health and health-care systems. It is thus imperative to fully understand the mechanisms that drive weight gain and its links to disease.

The MAP kinase-interacting kinases lie downstream of the classical ERK and stress-activated p38 MAP kinase pathways. Their best-known and only validated substrate is eukaryotic initiation factor-eIF4E, a protein which plays a crucial role in protein synthesis and its control. However, the physiological roles of the MNKs remain unclear.

There are two MNK genes in mammals. MNK2 is expressed at high levels in adipose tissue and liver, suggesting it may be involved in controlling metabolism. To test this, MNK2-knockout (KO) and wild-type mice were fed an energy-rich high-fat diet. While, as expected, HFD-fed wild-type mice show substantial weight gain and glucose intolerance, HFD-fed MNK2-KO mice are protected against both effects, and show lower fasting blood glucose and insulin levels. Wild-type mice also develop adipose tissue inflammation, whereas HFD-fed MNK2-KO mice are protected against this.

MNK2-KO mice fed a normal diet have fewer but larger fat cells, such that their basal fat mass is similar to that of wild-type mice. On a HFD, the fat cells of wild-type mice expand, but those of MNK2-KO mice do not. This may well explain why MNK2-KO mice are protected against weight gain. The smaller number of fat cells suggests MNK2 may play a role in adipogenesis. Indeed, data from the 3T3-L1 in vitro model of adipocyte differentiation strongly support the idea that MNK2 plays a crucial role in adipogenesis.

Our data reveal a novel role for the MNKs in adipose tissue biology and obesity. Given that MNKs are not essential for mouse viability, they are potential targets for the management of obesity and metabolic disease.