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
{"title":"NQO1 通过改善葡萄糖和脂质代谢保护肥胖小鼠。","authors":"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":"10.1038/s41514-020-00051-6","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>+</sup> 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.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.4000,"publicationDate":"2020-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678866/pdf/","citationCount":"0","resultStr":"{\"title\":\"NQO1 protects obese mice through improvements in glucose and lipid metabolism.\",\"authors\":\"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\":\"10.1038/s41514-020-00051-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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<sup>+</sup> 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.</p>\",\"PeriodicalId\":19334,\"journal\":{\"name\":\"NPJ Aging and Mechanisms of Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.4000,\"publicationDate\":\"2020-11-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678866/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"NPJ Aging and Mechanisms of Disease\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1038/s41514-020-00051-6\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Aging and Mechanisms of Disease","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1038/s41514-020-00051-6","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
NQO1 protects obese mice through improvements in glucose and lipid metabolism.
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.
期刊介绍:
npj Aging and Mechanisms of Disease is an online open access journal that provides a forum for the world’s most important research in the fields of aging and aging-related disease. The journal publishes papers from all relevant disciplines, encouraging those that shed light on the mechanisms behind aging and the associated diseases. The journal’s scope includes, but is not restricted to, the following areas (not listed in order of preference): • cellular and molecular mechanisms of aging and aging-related diseases • interventions to affect the process of aging and longevity • homeostatic regulation and aging • age-associated complications • translational research into prevention and treatment of aging-related diseases • mechanistic bases for epidemiological aspects of aging-related disease.