Disabling 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 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.

Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation

“…Nevertheless, treatments with ACA, Rapa or 17eE2 do not seem to affect any of the MAPK/ERK pathway protein levels, including MNK or eIF4E levels, in contrast to the upregulation of 4EBP1 protein [ 8 ] induced by these drugs. Recently it has been reported that reduction in MNK activity and the consequential decline in phosphorylation eIF4E improve glucose homeostasis [ 63 ], suggesting that some of the beneficial effects of these drugs and anti-aging genes may be under the control of the MAPK/ERK/eIF4E pathway. In addition, a reduction in the phosphorylation status of eIF4E (peIF4E) can upregulate the translation of a unique set of mRNAs [ 64 , 65 ], suggesting that some of the effects seen in previously published data in the upregulation of CIT proteins [ 8 ] by ACA, Rapa and 17aE2 could be, in part, the result of regulation of the MAPK/ERK/eIF4E signaling by the treatments.…”

“…In addition, a reduction in the phosphorylation status of eIF4E (peIF4E) can upregulate the translation of a unique set of mRNAs [ 64 , 65 ], suggesting that some of the effects seen in previously published data in the upregulation of CIT proteins [ 8 ] by ACA, Rapa and 17aE2 could be, in part, the result of regulation of the MAPK/ERK/eIF4E signaling by the treatments. However, a direct test of this hypothesis would require using the intervention protocols in the knockout model of the MAPK/ERK signaling, such is the MNK-KO mice [ 63 ].…”

Synthetic Retinoids as Potential Therapeutics in Prostate Cancer—An Update of the Last Decade of Research: A Review

“…Therefore, substances that eliminate its presence effectively reduce the proliferation of tumor cells. This seems to be particularly true, as simultaneous inhibition of Mnk1/2 leads to a switch to oxidative metabolism [ 67 ], which is associated with ROS production in cancer cells.…”

Design, Synthesis and Evaluation of Novel Phorbazole C Derivatives as MNK Inhibitors through Virtual High-Throughput Screening

“…Overexpression of eIF4E, p-eIF4E and MNKs has been found in various cancers [ 10 , 11 , 12 , 13 ], promoting cell proliferation, inducing cell migration and invasion, and regulating tumor microenvironment (TME) by increasing the secretion of proinflammatory cytokines [ 14 , 15 ]. Additionally, MNKs could prevent weight gain and enhance insulin sensitivity and energy expenditure in a high=fat diet [ 16 , 17 , 18 ]. Moreover, inhibition of MNKs impaired the Toll-like receptor (TLR) signaling pathways [ 15 ], cellular Type I and Type II interferon signaling [ 19 , 20 ], and decreased the production of IL-6, IL-10, MCP-1, etc.…”