npj Aging and Mechanisms of Disease (Nov 2020)
NQO1 protects obese mice through improvements in glucose and lipid metabolism
- 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
Affiliations
- Andrea Di Francesco
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Youngshim Choi
- Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health
- Michel Bernier
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Yingchun Zhang
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Alberto Diaz-Ruiz
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Miguel A. Aon
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Krystle Kalafut
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Margaux R. Ehrlich
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Kelsey Murt
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Ahmed Ali
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Kevin J. Pearson
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Sophie Levan
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Joshua D. Preston
- Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine
- Alejandro Martin-Montalvo
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- Jennifer L. Martindale
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Program, National Institutes of Health
- Kotb Abdelmohsen
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Program, National Institutes of Health
- Cole R. Michel
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
- Diana M. Willmes
- Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz German Center for Diabetes Research Munich, University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden
- Christine Henke
- Molecular Diabetology, Paul Langerhans Institute Dresden of the Helmholtz German Center for Diabetes Research Munich, University Hospital Carl Gustav Carus and Faculty of Medicine, TU Dresden
- Placido Navas
- Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide-CSIC-JA
- Jose Manuel Villalba
- Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario, ceiA3
- David Siegel
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
- Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Program, National Institutes of Health
- Kristofer Fritz
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
- Shyam Biswal
- Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health
- David Ross
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus
- Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging Intramural Program, National Institutes of Health
- DOI
- https://doi.org/10.1038/s41514-020-00051-6
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 18
Abstract
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.