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

doi:10.1038/s41514-020-00051-6

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 NavasJose Manuel Villalba, David Siegel, Myriam Gorospe, Kristofer Fritz, Shyam Biswal, David Ross, Rafael de Cabo

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20 Scopus citations

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.

Original language	English
Article number	13
Journal	npj Aging and Mechanisms of Disease
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s41514-020-00051-6
State	Published - Dec 2020

Bibliographical note

Funding Information:
We wish to thank Dawn Nines, Sarah Eckroth, and Sharon Ensor for expert animal care, and Marc Raley at NIA Visual Media Service. We gratefully acknowledge the contribution of the following scientific personnel for their excellent technical assistance: Donald S. Backos, Clara Di Germanio, Jessica M. Curtis, Maria del Mar Malagon, Frances Y. Fan, Vincent Gutierrez, Jacqueline M. Moats, Hector H. Palacios, Rajib Paul, Tyler Rhinesmith, Guri Tzivion, and Erin Wade. The work was funded, in part, by the Intramural Research Program of the National Institutes of Health/NIA and by grants #5R01CA206155 and R01ES031263 (S.B.), R01 DK109964 (D.R., K.F., R.d.C.).

Publisher Copyright:
© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

ASJC Scopus subject areas

Aging
Geriatrics and Gerontology

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10.1038/s41514-020-00051-6

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Di Francesco, A., Choi, Y., Bernier, M., Zhang, Y., Diaz-Ruiz, A., Aon, M. A., Kalafut, K., Ehrlich, M. R., Murt, K., Ali, A., Pearson, K. J., Levan, S., Preston, J. D., Martin-Montalvo, A., Martindale, J. L., Abdelmohsen, K., Michel, C. R., Willmes, D. M., Henke, C., ... de Cabo, R. (2020). NQO1 protects obese mice through improvements in glucose and lipid metabolism. npj Aging and Mechanisms of Disease, 6(1), Article 13. https://doi.org/10.1038/s41514-020-00051-6

@article{38a0f844bf7a4a82a9201aa10367b140,

title = "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 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.",

author = "{Di Francesco}, Andrea and Youngshim Choi and Michel Bernier and Yingchun Zhang and Alberto Diaz-Ruiz and Aon, {Miguel A.} and Krystle Kalafut and Ehrlich, {Margaux R.} and Kelsey Murt and Ahmed Ali and Pearson, {Kevin J.} and Sophie Levan and Preston, {Joshua D.} and Alejandro Martin-Montalvo and Martindale, {Jennifer L.} and Kotb Abdelmohsen and Michel, {Cole R.} and Willmes, {Diana M.} and Christine Henke and Placido Navas and Villalba, {Jose Manuel} and David Siegel and Myriam Gorospe and Kristofer Fritz and Shyam Biswal and David Ross and {de Cabo}, Rafael",

note = "Funding Information: We wish to thank Dawn Nines, Sarah Eckroth, and Sharon Ensor for expert animal care, and Marc Raley at NIA Visual Media Service. We gratefully acknowledge the contribution of the following scientific personnel for their excellent technical assistance: Donald S. Backos, Clara Di Germanio, Jessica M. Curtis, Maria del Mar Malagon, Frances Y. Fan, Vincent Gutierrez, Jacqueline M. Moats, Hector H. Palacios, Rajib Paul, Tyler Rhinesmith, Guri Tzivion, and Erin Wade. The work was funded, in part, by the Intramural Research Program of the National Institutes of Health/NIA and by grants #5R01CA206155 and R01ES031263 (S.B.), R01 DK109964 (D.R., K.F., R.d.C.). Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2020",

month = dec,

doi = "10.1038/s41514-020-00051-6",

language = "English",

volume = "6",

number = "1",

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Di Francesco, A, Choi, Y, Bernier, M, Zhang, Y, Diaz-Ruiz, A, Aon, MA, Kalafut, K, Ehrlich, MR, Murt, K, Ali, A, Pearson, KJ, Levan, S, Preston, JD, Martin-Montalvo, A, Martindale, JL, Abdelmohsen, K, Michel, CR, Willmes, DM, Henke, C, Navas, P, Villalba, JM, Siegel, D, Gorospe, M, Fritz, K, Biswal, S, Ross, D & de Cabo, R 2020, 'NQO1 protects obese mice through improvements in glucose and lipid metabolism', npj Aging and Mechanisms of Disease, vol. 6, no. 1, 13. https://doi.org/10.1038/s41514-020-00051-6

TY - JOUR

T1 - NQO1 protects obese mice through improvements in glucose and lipid metabolism

AU - Di Francesco, Andrea

AU - Choi, Youngshim

AU - Bernier, Michel

AU - Zhang, Yingchun

AU - Diaz-Ruiz, Alberto

AU - Aon, Miguel A.

AU - Kalafut, Krystle

AU - Ehrlich, Margaux R.

AU - Murt, Kelsey

AU - Ali, Ahmed

AU - Pearson, Kevin J.

AU - Levan, Sophie

AU - Preston, Joshua D.

AU - Martin-Montalvo, Alejandro

AU - Martindale, Jennifer L.

AU - Abdelmohsen, Kotb

AU - Michel, Cole R.

AU - Willmes, Diana M.

AU - Henke, Christine

AU - Navas, Placido

AU - Villalba, Jose Manuel

AU - Siegel, David

AU - Gorospe, Myriam

AU - Fritz, Kristofer

AU - Biswal, Shyam

AU - Ross, David

AU - de Cabo, Rafael

N1 - Funding Information: We wish to thank Dawn Nines, Sarah Eckroth, and Sharon Ensor for expert animal care, and Marc Raley at NIA Visual Media Service. We gratefully acknowledge the contribution of the following scientific personnel for their excellent technical assistance: Donald S. Backos, Clara Di Germanio, Jessica M. Curtis, Maria del Mar Malagon, Frances Y. Fan, Vincent Gutierrez, Jacqueline M. Moats, Hector H. Palacios, Rajib Paul, Tyler Rhinesmith, Guri Tzivion, and Erin Wade. The work was funded, in part, by the Intramural Research Program of the National Institutes of Health/NIA and by grants #5R01CA206155 and R01ES031263 (S.B.), R01 DK109964 (D.R., K.F., R.d.C.). Publisher Copyright: © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

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U2 - 10.1038/s41514-020-00051-6

DO - 10.1038/s41514-020-00051-6

M3 - Article

AN - SCOPUS:85096296676

VL - 6

JO - npj Aging and Mechanisms of Disease

JF - npj Aging and Mechanisms of Disease

IS - 1

M1 - 13

ER -

NQO1 protects obese mice through improvements in glucose and lipid metabolism

Abstract

Bibliographical note

ASJC Scopus subject areas

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