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.

中文翻译：

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MAPK相互作用激酶2（MNK2）调节脂肪细胞的代谢，与其催化活性无关。

丝裂原激活蛋白激酶（MAPK）相互作用激酶（MNK）是丝氨酸/苏氨酸蛋白激酶，可通过ERK1 / 2（细胞外调节激酶）和p38α/βMAPK途径激活。MNK以前与代谢性疾病有关，并显示出介导饮食诱导的肥胖症。特别是，敲除小鼠中的MNK2可以防止高脂饮食诱导的体重增加。这些和其他数据表明，MNK2调节脂肪组织（AT）的膨胀，这是一种稳定的长期能量储备，在调节全身能量稳态中起着重要作用。使用成熟的小鼠3T3-L1脂肪形成体外模型，研究了MNK在脂肪细胞分化和脂质存储中的作用。使用特定抑制剂抑制MNK活性不能损害脂肪形成或脂质积聚，这表明MNK活性不是脂肪细胞分化所必需的，也不调节脂质的储存。然而，MNK2的小干扰RNA（siRNA）敲低确实减少了脂质的积累，并调节了两个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（Lipin-1）的水平。这些因素负责控制涉及从头脂肪形成和甘油三酸酯合成的蛋白质的基因表达。MNK2的敲低还增加了激素敏感性脂肪酶的表达，其催化甘油三酸酯的分解。这些发现确定MNK2是脂肪细胞代谢的调节剂，与其催化活性无关，并揭示了MNK2驱动AT扩展的一些机制。因此，开发针对MNK2的疗法可能是减轻因过多营养摄入而导致体重减轻的有用干预措施。