NQO1 protects obese mice through improvements in glucose and lipid metabolism
Abstract Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection f...
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Format: | Article |
Language: | English |
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Nature Publishing Group
2020-11-01
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Series: | npj Aging and Mechanisms of Disease |
Online Access: | https://doi.org/10.1038/s41514-020-00051-6 |
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doaj-fcd69445e0874cb1841372862929c6f9 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrea Di Francesco Youngshim Choi Michel Bernier Yingchun Zhang Alberto Diaz-Ruiz Miguel A. Aon Krystle Kalafut Margaux R. Ehrlich Kelsey Murt Ahmed Ali Kevin J. Pearson Sophie Levan Joshua D. Preston Alejandro Martin-Montalvo Jennifer L. Martindale Kotb Abdelmohsen Cole R. Michel Diana M. Willmes Christine Henke Placido Navas Jose Manuel Villalba David Siegel Myriam Gorospe Kristofer Fritz Shyam Biswal David Ross Rafael de Cabo |
spellingShingle |
Andrea Di Francesco Youngshim Choi Michel Bernier Yingchun Zhang Alberto Diaz-Ruiz Miguel A. Aon Krystle Kalafut Margaux R. Ehrlich Kelsey Murt Ahmed Ali Kevin J. Pearson Sophie Levan Joshua D. Preston Alejandro Martin-Montalvo Jennifer L. Martindale Kotb Abdelmohsen Cole R. Michel Diana M. Willmes Christine Henke Placido Navas Jose Manuel Villalba David Siegel Myriam Gorospe Kristofer Fritz Shyam Biswal David Ross Rafael de Cabo NQO1 protects obese mice through improvements in glucose and lipid metabolism npj Aging and Mechanisms of Disease |
author_facet |
Andrea Di Francesco Youngshim Choi Michel Bernier Yingchun Zhang Alberto Diaz-Ruiz Miguel A. Aon Krystle Kalafut Margaux R. Ehrlich Kelsey Murt Ahmed Ali Kevin J. Pearson Sophie Levan Joshua D. Preston Alejandro Martin-Montalvo Jennifer L. Martindale Kotb Abdelmohsen Cole R. Michel Diana M. Willmes Christine Henke Placido Navas Jose Manuel Villalba David Siegel Myriam Gorospe Kristofer Fritz Shyam Biswal David Ross Rafael de Cabo |
author_sort |
Andrea Di Francesco |
title |
NQO1 protects obese mice through improvements in glucose and lipid metabolism |
title_short |
NQO1 protects obese mice through improvements in glucose and lipid metabolism |
title_full |
NQO1 protects obese mice through improvements in glucose and lipid metabolism |
title_fullStr |
NQO1 protects obese mice through improvements in glucose and lipid metabolism |
title_full_unstemmed |
NQO1 protects obese mice through improvements in glucose and lipid metabolism |
title_sort |
nqo1 protects obese mice through improvements in glucose and lipid metabolism |
publisher |
Nature Publishing Group |
series |
npj Aging and Mechanisms of Disease |
issn |
2056-3973 |
publishDate |
2020-11-01 |
description |
Abstract Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD+ metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits. |
url |
https://doi.org/10.1038/s41514-020-00051-6 |
work_keys_str_mv |
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doaj-fcd69445e0874cb1841372862929c6f92021-04-02T19:02:23ZengNature Publishing Groupnpj Aging and Mechanisms of Disease2056-39732020-11-016111810.1038/s41514-020-00051-6NQO1 protects obese mice through improvements in glucose and lipid metabolismAndrea Di Francesco0Youngshim Choi1Michel Bernier2Yingchun Zhang3Alberto Diaz-Ruiz4Miguel A. Aon5Krystle Kalafut6Margaux R. Ehrlich7Kelsey Murt8Ahmed Ali9Kevin J. Pearson10Sophie Levan11Joshua D. Preston12Alejandro Martin-Montalvo13Jennifer L. Martindale14Kotb Abdelmohsen15Cole R. Michel16Diana M. Willmes17Christine Henke18Placido Navas19Jose Manuel Villalba20David Siegel21Myriam Gorospe22Kristofer Fritz23Shyam Biswal24David Ross25Rafael de Cabo26Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthPharmacology and Nutritional Sciences, University of Kentucky College of MedicineTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthLaboratory of Genetics and Genomics, National Institute on Aging Intramural Program, National Institutes of HealthLaboratory of Genetics and Genomics, National Institute on Aging Intramural Program, National Institutes of HealthDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusMolecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz German Center for Diabetes Research Munich, University Hospital Carl Gustav Carus and Faculty of Medicine, TU DresdenMolecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz German Center for Diabetes Research Munich, University Hospital Carl Gustav Carus and Faculty of Medicine, TU DresdenCentro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JADepartamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusLaboratory of Genetics and Genomics, National Institute on Aging Intramural Program, National Institutes of HealthDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusDepartment of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public HealthDepartment of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical CampusTranslational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of HealthAbstract Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD+ metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.https://doi.org/10.1038/s41514-020-00051-6 |