NQO1 protects obese mice through improvements in glucose and lipid metabolism
Andrea Di Francesco, Youngshim Choi, Michel Bernier, Yingchun Zhang, Alberto Díaz‐Ruiz, Miguel A. Aon, Krystle C. Kalafut, Margaux R. Ehrlich, Kelsey N. Murt, Ahmed Ali, Kevin J. Pearson, Sophia Levan, Joshua D. Preston, Alejandro Martín‐Montalvo, Jennifer L. Martindale, Kotb Abdelmohsen, Cole R. Michel, Diana M. Willmes, Christine Henke, Plácido Navas, José M. Villalba, David Siegel, Myriam Gorospe, Kristofer S. Fritz, Shyam Biswal, David Ross, Rafael de Cabo
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.