NQO1 protects obese mice through improvements in glucose and lipid metabolism

• Type of Material: Article
• Authors: Andrea Di Francesco, National Institutes of Health; Youngshim Choi, Johns Hopkins University; Michel Bernier, National Institutes of Health; Yingchun Zhang, National Institutes of Health; Alberto Diaz-Ruiz, National Institutes of Health; Miguel A. Aon, National Institutes of Health; Krystle Kalafut, National Institutes of Health; Marguex R. Ehrlich, National Institutes of Health; David Ross, Emory University; Rafael de Cabo, National Institutes of Health
• Language: English
• Date: 2020-11-19
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41514-020-00051-6
• Title of Journal or Parent Work: npj Aging and Mechanisms of Disease
• Volume: 6
• Grant/Funding Information: 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.).
• Keywords: Obesity; Diabetes
• Research Categories: Health Sciences, Public Health; Health Sciences, Nutrition

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.