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

DOI
https://doi.org/10.1038/s41514-020-00051-6
Journal volume & issue
Vol. 6, no. 1
pp. 1 – 18

Abstract

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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.