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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476876/ https://www.ncbi.nlm.nih.gov/pubmed/32712434 http://dx.doi.org/10.1016/j.molmet.2020.101054 |
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author | Sandeman, Lauren Y. Kang, Wan Xian Wang, Xuemin Jensen, Kirk B. Wong, Derick Bo, Tao Gao, Ling Zhao, Jiajun Byrne, Christopher D. Page, Amanda J. Proud, Christopher G. |
author_facet | Sandeman, Lauren Y. Kang, Wan Xian Wang, Xuemin Jensen, Kirk B. Wong, Derick Bo, Tao Gao, Ling Zhao, Jiajun Byrne, Christopher D. Page, Amanda J. Proud, Christopher G. |
author_sort | Sandeman, Lauren Y. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7476876 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-74768762020-09-15 Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity Sandeman, Lauren Y. Kang, Wan Xian Wang, Xuemin Jensen, Kirk B. Wong, Derick Bo, Tao Gao, Ling Zhao, Jiajun Byrne, Christopher D. Page, Amanda J. Proud, Christopher G. Mol Metab Original Article 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. Elsevier 2020-07-23 /pmc/articles/PMC7476876/ /pubmed/32712434 http://dx.doi.org/10.1016/j.molmet.2020.101054 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Sandeman, Lauren Y. Kang, Wan Xian Wang, Xuemin Jensen, Kirk B. Wong, Derick Bo, Tao Gao, Ling Zhao, Jiajun Byrne, Christopher D. Page, Amanda J. Proud, Christopher G. Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity |
title | Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity |
title_full | Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity |
title_fullStr | Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity |
title_full_unstemmed | Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity |
title_short | Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity |
title_sort | disabling mnk protein kinases promotes oxidative metabolism and protects against diet-induced obesity |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476876/ https://www.ncbi.nlm.nih.gov/pubmed/32712434 http://dx.doi.org/10.1016/j.molmet.2020.101054 |
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