NQO1 protects obese mice through improvements in glucose and lipid metabolism

Andrea Di Francesco,Joshua D Preston,David Siegel,Kelsey N Murt ,José M Villalba ,Sophie Levan,David Ross,Margaux R Ehrlich,Yingchun Zhang,Kevin J Pearson,Kristofer S Fritz ,Shyam Biswal,Miguel A Aon,Jennifer L Martindale,Youngshim Choi,Kotb Abdelmohsen,Alberto Díaz‐Ruiz ,Cole Michel ,Plácido Navas ,Aléjandro Martín-Montalvo ,Myriam Gorospe,Diana M Willmes,Michel Bernier,Christine Henke,Krystle Kalafut,Ahmed Ali,Rafael De Cabo

doi:10.1038/s41514-020-00051-6

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.

Highlights

Diet-induced obesity is a risk factor for elevated cardiovascular mortality and type 2 diabetes (T2D), and a contributor to increased morbidities such as cancer, and chronic liver and kidney diseases
These data indicate that NAD(P)H:quinone oxidoreductase 1 (NQO1) exhibited major maturational growth rate has nearly plateaued
Consumption of high-fat diet (HFD) was associated with higher heat production in mice of both genotypes (Supplementary Fig. 2h). These results reveal that NQO1 transgenic mice exhibit significant improvements in glucose homeostasis and insulin sensitivity without obvious changes in body composition, food intake, and overall metabolic flexibility compared to WT littermates when fed HFD

Summary

Introduction

Diet-induced obesity is a risk factor for elevated cardiovascular mortality and type 2 diabetes (T2D), and a contributor to increased morbidities such as cancer, and chronic liver and kidney diseases. While 80% of individuals diagnosed with T2D are obese, yet not all obese individuals develop this metabolic condition[1]. The transcription factor nuclear factor erythroid-2-related factor 2 Nfe2l2 ( known as Nrf2) is a critical mediator of the cellular response to environmental stress. Exposure to a number of stressors, including electrophiles, reactive oxidative species, heavy metals, and xenobiotics leads to conformational changes in Keap[1], enabling stabilization and nuclear accumulation of Nrf[2], where it coordinates the expression of multiple cellular defense enzymes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1), and key components of the glutathione (GSH) and thioredoxin (TXN) antioxidant systems[2]

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Results

Conclusion