Lifelong Health, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
Biochem J. 2020 Jul 31;477(14):2735-2754. doi: 10.1042/BCJ20200433.
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.
丝裂原活化蛋白激酶（MAPK）相互作用激酶（MNKs）是丝氨酸/苏氨酸蛋白激酶，可被 ERK1/2（细胞外调节激酶）和 p38α/β MAPK 途径激活。MNKs 先前被牵连到代谢疾病中，并被证明介导饮食诱导的肥胖。特别是，在小鼠中敲除 MNK2 可防止高脂肪饮食引起的体重增加。这些和其他数据表明，MNK2 调节脂肪组织（AT）的扩张，AT 是一种稳定的长期能量储备，在调节全身能量平衡中起着重要作用。使用成熟的体外 3T3-L1 脂肪生成模型，研究了 MNKs 在脂肪细胞分化和脂质储存中的作用。使用特异性抑制剂抑制 MNK 活性未能损害脂肪生成或脂质积累，表明 MNK 活性不是脂肪细胞分化所必需的，也不调节脂质储存。然而，MNK2 的小干扰 RNA（siRNA）敲低确实减少了脂质积累，并调节了两种主要的脂肪生成转录调节因子，ChREBP（碳水化合物反应元件结合蛋白）和 LPIN1（脂肪酶抑制剂 1）的水平。这些因子负责控制参与从头脂肪生成和甘油三酯合成的蛋白质的基因表达。MNK2 的敲低还增加了激素敏感脂肪酶的表达，该酶催化甘油三酯的分解。这些发现确定 MNK2 是脂肪细胞代谢的调节剂，独立于其催化活性，并揭示了 MNK2 驱动 AT 扩张的一些机制。因此，开发针对 MNK2 的治疗方法可能是减少过度营养摄入引起的体重的有用干预措施。
