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The mechanistic interrelationship between altered energy metabolism, remodeling, and function remains unclear. The ROS-generating NADPH oxidase-4 (Nox4) is upregulated in the overloaded heart, where it ameliorates adverse remodeling. Here, we show that Nox4 redirects glucose metabolism away from oxidation but increases fatty acid oxidation, thereby maintaining cardiac energetics during acute or chronic stresses. The changes in glucose and fatty acid metabolism are interlinked via a Nox4-ATF4\u2013dependent increase in the hexosamine biosynthetic pathway, which mediates the attachment of O-linked N-acetylglucosamine (O-GlcNAcylation) to the fatty acid transporter CD36 and enhances fatty acid utilization. These data uncover a potentially novel redox pathway that regulates protein O-GlcNAcylation and reprograms cardiac substrate metabolism to favorably modify adaptation to chronic stress. Our results also suggest that increased fatty acid oxidation in the chronically stressed heart may be beneficial.<\/jats:p>","DOI":"10.1172\/jci.insight.96184","type":"journal-article","created":{"date-parts":[[2017,12,20]],"date-time":"2017-12-20T11:01:44Z","timestamp":1513767704000},"source":"Crossref","is-referenced-by-count":55,"title":["Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation"],"prefix":"10.1172","volume":"2","author":[{"given":"Adam A.","family":"Nabeebaccus","sequence":"first","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Zoccarato","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne D.","family":"Hafstad","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."},{"name":"Cardiovascular Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Troms\u00f8, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celio X.C.","family":"Santos","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5731-3273","authenticated-orcid":true,"given":"Ellen","family":"Aasum","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Troms\u00f8, Norway."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison C.","family":"Brewer","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Beretta","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5172-0935","authenticated-orcid":true,"given":"Xiaoke","family":"Yin","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"West","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3099-526X","authenticated-orcid":true,"given":"Katrin","family":"Schr\u00f6der","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Kardiovaskul\u00e4re Physiologie, Goethe-Universit\u00e4t, Frankfurt am Main, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1336-7744","authenticated-orcid":true,"given":"Julian L.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas R.","family":"Eykyn","sequence":"additional","affiliation":[{"name":"Division of Imaging Sciences & Biomedical Engineering, King\u2019s College London British Heart Foundation Centre of Excellence, London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5290-0738","authenticated-orcid":true,"given":"E. 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