Objectives

Diet-driven obesity is increasingly widespread. Its consequences pose major challenges to human health and health care systems. There are MAP kinase-interacting kinases (MNKs) in mice, MNK1 and MNK2. Studies have demonstrated that mice lacking either MNK1 or MNK2 were partially protected against high-fat diet (HFD)-induced weight gain and insulin resistance. The aims of this study were to evaluate the phenotype of mice lacking both MNKs when given an HFD, to assess whether pharmacological inhibition of MNK function also protects against diet-induced obesity (DIO) and its consequences and to probe the mechanisms underlying such protection.

Methods

Male wild-type (WT) C57Bl6 mice or mice lacking both MNK1 and MNK2 (double knockout, DKO) were fed an HFD or control diet (CD) for up to 16 weeks.

In a separate study, WT mice were also given an HFD for 6 weeks, after which half were treated with the recently-developed MNK inhibitor ETC-206 daily for 10 more weeks while continuing an HFD. Metabolites and other parameters were measured, and the expression of selected mRNAs and proteins was assessed.

Results

MNK-DKO mice were almost completely protected from HFD-induced obesity. Higher energy expenditure (EE) in MNK-DKO mice was observed, which probably reflects the changes in a number of genes or proteins linked to lipolysis, mitochondrial function/biogenesis, oxidative metabolism, and/or ATP consumption. The MNK inhibitor ETC-206 also prevented HFD-induced weight gain, confirming that the activity of the MNKs facilitates weight gain due to excessive caloric consumption.

Conclusions

Disabling MNKs in mice, either genetically or pharmacologically, strongly prevents weight gain on a calorie-rich diet. This finding likely results from increased energy utilisation, involving greater ATP consumption, mitochondrial oxidative metabolism, and other processes.

中文翻译：

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禁用 MNK 蛋白激酶可促进氧化代谢并防止饮食引起的肥胖。

目标

饮食驱动的肥胖症越来越普遍。其后果对人类健康和医疗保健系统构成重大挑战。小鼠中有 MAP 激酶相互作用激酶 (MNK)，MNK1 和 MNK2。研究表明，缺乏 MNK1 或 MNK2 的小鼠部分受到保护，免受高脂肪饮食 (HFD) 诱导的体重增加和胰岛素抵抗。本研究的目的是评估在给予 HFD 时缺乏两种 MNK 的小鼠的表型，评估 MNK 功能的药理学抑制是否也能防止饮食诱导的肥胖 (DIO) 及其后果，并探讨这种保护的潜在机制。

方法

雄性野生型 (WT) C57Bl6 小鼠或缺乏 MNK1 和 MNK2（双基因敲除，DKO）的小鼠被喂食 HFD 或对照饮食（CD）长达 16 周。

在另一项研究中，WT 小鼠也接受了 6 周的 HFD，之后一半每天用最近开发的 MNK 抑制剂 ETC-206 治疗 10 周以上，同时继续 HFD。测量代谢物和其他参数，并评估所选 mRNA 和蛋白质的表达。

结果

MNK-DKO 小鼠几乎完全免受 HFD 诱导的肥胖。在 MNK-DKO 小鼠中观察到更高的能量消耗 (EE)，这可能反映了与脂肪分解、线粒体功能/生物发生、氧化代谢和/或 ATP 消耗相关的许多基因或蛋白质的变化。MNK 抑制剂 ETC-206 还阻止了 HFD 诱导的体重增加，证实了 MNK 的活性促进了由于热量消耗过多而导致的体重增加。

结论

在小鼠体内禁用 MNK，无论是在基因上还是在药理学上，都可以极大地防止高热量饮食中的体重增加。这一发现可能是由于能量利用增加，涉及更多的 ATP 消耗、线粒体氧化代谢和其他过程。