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.
|Journal||npj Aging and Mechanisms of Disease|
|State||Published - Dec 2020|
Bibliographical noteFunding 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.).
© 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
- Geriatrics and Gerontology