Disabling the MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity

Abstract Objectives Diet-driven obesity is increasingly widespread. Its consequences pose major challenges both to human health and health-care systems. There are two MAP kinase-interacting kinases (MNKs) in mice, MNK1 and MNK2. Previous studies showed 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 a 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 HFD or control diet (CD) for up to 16 weeks. In a separate study, WT mice were also given HFD for 6 weeks, after which half were treated with the recently-developed MNK inhibitor ETC-206 daily for 10 more weeks, whilst maintained on a 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 likely 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 the MNKs in mice, either genetically or pharmacologically, strongly prevents weight gain on a calorie-rich diet. This likely results from increased energy utilisation, involving greater ATP consumption, mitochondrial oxidative metabolism and other processes.