Vitamin B2 enables regulation of fasting glucose availability
Peter M Masschelin,
Pradip Saha,
Scott A Ochsner,
Aaron R Cox,
Kang Ho Kim,
Jessica B Felix,
Robert Sharp,
Xin Li,
Lin Tan,
Jun Hyoung Park,
Liping Wang,
Vasanta Putluri,
Philip L Lorenzi,
Alli M Nuotio-Antar,
Zheng Sun,
Benny Abraham Kaipparettu,
Nagireddy Putluri,
David D Moore,
Scott A Summers,
Neil J McKenna,
Sean M Hartig
Affiliations
Peter M Masschelin
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
Pradip Saha
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States
Scott A Ochsner
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
Aaron R Cox
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States
Kang Ho Kim
Department of Anesthesiology, University of Texas Health Sciences Center, Houston, United States
Jessica B Felix
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
Robert Sharp
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States
Lin Tan
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, United States
Jun Hyoung Park
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States
Benny Abraham Kaipparettu
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
Nagireddy Putluri
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
David D Moore
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, United States
Scott A Summers
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States
Neil J McKenna
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
Department of Diabetes, Endocrinology, and Metabolism, Baylor College of Medicine, Houston, United States; Department of Medicine, Baylor College of Medicine, Houston, United States; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States
Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. 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 PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα 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.