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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820301289 |
| _version_ | 1818655750822559744 |
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| author | Lauren Y. Sandeman Wan Xian Kang Xuemin Wang Kirk B. Jensen Derick Wong Tao Bo Ling Gao Jiajun Zhao Christopher D. Byrne Amanda J. Page Christopher G. Proud |
| author_facet | Lauren Y. Sandeman Wan Xian Kang Xuemin Wang Kirk B. Jensen Derick Wong Tao Bo Ling Gao Jiajun Zhao Christopher D. Byrne Amanda J. Page Christopher G. Proud |
| author_sort | Lauren Y. Sandeman |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-17T03:14:39Z |
| format | Article |
| id | doaj.art-dbedafa795c94829810cffac9457bea6 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-17T03:14:39Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-dbedafa795c94829810cffac9457bea62022-12-21T22:05:44ZengElsevierMolecular Metabolism2212-87782020-12-0142101054Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesityLauren Y. Sandeman0Wan Xian Kang1Xuemin Wang2Kirk B. Jensen3Derick Wong4Tao Bo5Ling Gao6Jiajun Zhao7Christopher D. Byrne8Amanda J. Page9Christopher G. Proud10Lifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, AustraliaLifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, AustraliaLifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia; School of Biomedical Sciences, University of Adelaide, Adelaide, SA, 5005, AustraliaLifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia; School of Biomedical Sciences, University of Adelaide, Adelaide, SA, 5005, AustraliaLifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, AustraliaLifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia; Shandong-South Australia Joint Laboratory of Metabolic Disease Research, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, ChinaShandong-South Australia Joint Laboratory of Metabolic Disease Research, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, ChinaShandong-South Australia Joint Laboratory of Metabolic Disease Research, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, ChinaHuman Development and Health, Faculty of Medicine, University of Southampton, Southampton, Hampshire, SO16 6YD, UK; National Institute for Health Research Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton National Health Service Foundation Trust, Southampton, Hampshire, SO17 1BJ, UKLifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia; Vagal Afferent Research Group, Centre for Nutrition and Gastrointestinal Diseases, Adelaide Medical School, Adelaide, SA, 5000, AustraliaLifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia; School of Biomedical Sciences, University of Adelaide, Adelaide, SA, 5005, Australia; Corresponding author. Lifelong Health, South Australian Health & Medical Research Institute, Adelaide, SA, 5000, Australia.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.http://www.sciencedirect.com/science/article/pii/S2212877820301289Adipose tissueDiet-induced obesityMNKLipid metabolismMitochondriaEnergy expenditure |
| spellingShingle | Lauren Y. Sandeman Wan Xian Kang Xuemin Wang Kirk B. Jensen Derick Wong Tao Bo Ling Gao Jiajun Zhao Christopher D. Byrne Amanda J. Page Christopher G. Proud Disabling MNK protein kinases promotes oxidative metabolism and protects against diet-induced obesity Molecular Metabolism Adipose tissue Diet-induced obesity MNK Lipid metabolism Mitochondria Energy expenditure |
| 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 | Adipose tissue Diet-induced obesity MNK Lipid metabolism Mitochondria Energy expenditure |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820301289 |
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