Abstract
The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are serine/threonine protein kinases that are activated by the ERK1/2 (extracellular regulated kinase) and p38α/β MAPK pathways. The MNKs have previously been implicated in metabolic disease and shown to mediate diet-induced obesity. In particular, knockout of MNK2 in mice protects from the weight gain induced by a high-fat diet. These and other data suggest that MNK2 regulates the expansion of adipose tissue (AT), a stable, long-term energy reserve that plays an important role in regulating whole-body energy homeostasis. Using the well-established mouse 3T3-L1 in vitro model of adipogenesis, the role of the MNKs in adipocyte differentiation and lipid storage was investigated. Inhibition of MNK activity using specific inhibitors failed to impair adipogenesis or lipid accumulation, suggesting that MNK activity is not required for adipocyte differentiation and does not regulate lipid storage. However, small-interfering RNA (siRNA) knock-down of MNK2 did reduce lipid accumulation and regulated the levels of two major lipogenic transcriptional regulators, ChREBP (carbohydrate response element-binding protein) and LPIN1 (Lipin-1). These factors are responsible for controlling the expression of genes for proteins involved in de novo lipogenesis and triglyceride synthesis. The knock-down of MNK2 also increased the expression of hormone-sensitive lipase which catalyses the breakdown of triglyceride. These findings identify MNK2 as a regulator of adipocyte metabolism, independently of its catalytic activity, and reveal some of the mechanisms by which MNK2 drives AT expansion. The development of an MNK2-targeted therapy may, therefore, be a useful intervention for reducing weight caused by excessive nutrient intake.
Highlights
In animals, highly integrated systems have evolved to promote storage during periods of energy abundance and to mobilise stores during periods of energy deprivation and demand [1]
To study the individual contributions of MNK1 and MNK2 to adipocyte differentiation, small-interfering RNA (siRNA) directed against Mknk1 and Mknk2 were employed
Given eFT508 did not elicit the same changes in gene expression as observed in MNK2 knock-down adipocytes, the observed metabolic changes associated with MNK2 knock-down are suggested to be mediated by a non-catalytic function(s) of MNK2. These studies were prompted by our striking observation that MNK2-KO mice are substantially protected against the weight gain that is usually induced by consuming a high-fat diet (HFD) [12]
Summary
Highly integrated systems have evolved to promote storage during periods of energy abundance and to mobilise stores during periods of energy deprivation and demand [1]. Excessive nutrient intake relative to expenditure produces a metabolic state that promotes energy storage; in the context of adipose tissue (AT), this results in adipocyte hyperplasia and hypertrophy [2]; hyperplasia involves recruitment of stem cells and their differentiation to the adipocyte lineage (adipogenesis), whereas hypertrophy involves the expansion of existing adipocyte triglyceride (TAG) stores. Established protocols have been developed to initiate the differentiation of pre-adipocytes; inducers that activate the insulin [5], glucocorticoid and cyclic adenosine monophosphate (cAMP)-signalling pathways [4,6,7] initiate a phase of early transcription, which is followed by synchronous entry into the cell cycle and several rounds of mitosis. Upon exit from the cell cycle, cells lose their fibroblastic morphology, accumulate TAG and acquire the metabolic features and appearance of adipocytes [5,8]. TAG accumulation is closely correlated with an increased rate of de novo lipogenesis (DNL) and a co-ordinate rise in expression of the enzymes of fatty acid (FA) and TAG biosynthesis [9]
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