MAPK-interacting kinase 2 (MNK2) regulates adipocyte metabolism independently of its catalytic activity

James E. Merrett, Jianling Xie, Peter J. Psaltis, Christopher G. Proud

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2735-2754
Number of pages20
JournalThe Biochemical journal
Volume477
Issue number14
DOIs
Publication statusPublished - 31 Jul 2020

Keywords

  • adipocytes
  • adipogenesis
  • metabolism
  • MNK
  • triglycerides

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