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Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPAR\u03b1, including those required for gluconeogenesis. We also found PPAR\u03b1 knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPAR\u03b1 agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.<\/jats:p>","DOI":"10.7554\/elife.84077","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T03:15:13Z","timestamp":1687749313000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.84077","source":"Crossref","is-referenced-by-count":14,"title":["Vitamin B2 enables regulation of fasting glucose availability"],"prefix":"10.7554","volume":"12","author":[{"given":"Peter M","family":"Masschelin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine","place":["Houston, United States"]},{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicine, Baylor College of Medicine","place":["Houston, United 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