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

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

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.

Adipose tissue, Diet-induced obesity, Energy expenditure, Lipid metabolism, MNK, Mitochondria
Sandeman, Lauren Y.
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Kang, Wan Xian
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Wang, Xuemin
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Jensen, Kirk B.
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Wong, Derick
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Bo, Tao
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Gao, Ling
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Zhao, Jiajun
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Byrne, Christopher
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Page, Amanda J.
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Proud, Christopher G.
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Sandeman, Lauren Y.
6c8e188b-73e2-41b8-a815-b3509820d178
Kang, Wan Xian
7b05dcdb-6dbe-4f3a-8102-dcd1c003b58b
Wang, Xuemin
240a490e-64f4-431d-88d3-f0348f7a52ee
Jensen, Kirk B.
fc21202b-fd1c-4583-9622-c155e8feb63f
Wong, Derick
ce5c5b00-03d2-43bf-8949-db8a9be1d959
Bo, Tao
ddff83a1-fd67-4501-a9a5-482057cf27e7
Gao, Ling
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Zhao, Jiajun
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Byrne, Christopher
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Page, Amanda J.
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Proud, Christopher G.
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Sandeman, Lauren Y., Kang, Wan Xian, Wang, Xuemin, Jensen, Kirk B., Wong, Derick, Bo, Tao, Gao, Ling, Zhao, Jiajun, Byrne, Christopher, Page, Amanda J. and Proud, Christopher G. (2020) Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity. Molecular Metabolism, 42, [101054]. (doi:10.1016/j.molmet.2020.101054).

Record type: Article

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.

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More information

Accepted/In Press date: 20 July 2020
e-pub ahead of print date: 23 July 2020
Published date: December 2020
Additional Information: Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.
Keywords: Adipose tissue, Diet-induced obesity, Energy expenditure, Lipid metabolism, MNK, Mitochondria

Identifiers

Local EPrints ID: 442916
URI: http://eprints.soton.ac.uk/id/eprint/442916
PURE UUID: f709ac2c-8e68-4e29-bbed-508807622770
ORCID for Christopher Byrne: ORCID iD orcid.org/0000-0001-6322-7753

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Date deposited: 31 Jul 2020 16:30
Last modified: 28 Apr 2022 01:45

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Contributors

Author: Lauren Y. Sandeman
Author: Wan Xian Kang
Author: Xuemin Wang
Author: Kirk B. Jensen
Author: Derick Wong
Author: Tao Bo
Author: Ling Gao
Author: Jiajun Zhao
Author: Amanda J. Page
Author: Christopher G. Proud

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