Vitamin B2 enables regulation of fasting glucose availability

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 PPAR alpha, including those required for gluconeogenesis. We also found PPAR alpha knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPAR alpha 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.

Automated summary

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions for cellular energy demands. Depleting FAD pools in mice causes phenotypes associated with organic acidemias and other inborn errors of metabolism (IEMs), such as reduced body weight, hypoglycemia, and fatty liver disease. The study reveals that B2D inhibits fasting activation of PPAR alpha target genes and downregulates gluconeogenesis genes. Knockdown of PPAR alpha in the liver recapitulates B2D effects, while treatment with the PPAR alpha agonist fenofibrate rescues fasting glucose availability and overcomes B2D phenotypes.