Vitamin B2 enables regulation of fasting glucose availability

Authors: MASSCHELIN, PETER - Baylor College Of Medicine; SAHA, PRADIP - Baylor College Of Medicine; OCHSNER, SCOTT - Baylor College Of Medicine; COX, AARON - Baylor College Of Medicine; KIM, KANG - University Of Texas Health Science Center; FELIX, JESSICA - Baylor College Of Medicine; SHARP, ROBERT - Baylor College Of Medicine; LI, XIN - Baylor College Of Medicine; TAN, LIN - University Of Texas; PARK, JUN - Baylor College Of Medicine; WANG, LIPING - University Of Utah; PUTLURI, VASANTA - Baylor College Of Medicine; LORENZI, PHILIP - University Of Texas; NUOTIO-ANTAR, ALLI - Children'S Nutrition Research Center (CNRC); SUN, ZHENG - Baylor College Of Medicine; KAIPPARETTU, BENNYA - Baylor College Of Medicine; PUTLURI, NAGIREDDY - Baylor College Of Medicine; MOORE, DAVID - Baylor College Of Medicine; SUMMERS, SCOTT - University Of Utah; MCKENNA, NEIL - Baylor College Of Medicine; HARTIG, SEAN - Baylor College Of Medicine

Submitted to: eLife
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/24/2023
Publication Date: 2/7/2023
Citation: Masschelin, P.M., Saha, P., Ochsner, S.A., Cox, A.R., Kim, K.H., Felix, J.B., Sharp, R., Li, X., Tan, L., Park, J.H., Wang, L., Putluri, V., Lorenzi, P.L., Nuotio-Antar, A.M., Sun, Z., Kaipparettu, B.A., Putluri, N., Moore, D.D., Summers, S.A., McKenna, N.J., Hartig, S.M. 2023. Vitamin B2 enables regulation of fasting glucose availability. eLife. 12. Article e84077. https://doi.org/10.7554/eLife.84077.
DOI: https://doi.org/10.7554/eLife.84077

Interpretive Summary: Riboflavin, also known as vitamin B2, regulates flavin adenine dinucleotide (FAD), which is important for cellular energy. Mice fed a riboflavin-deficient diet do not gain weight, are unable to produce adequate glucose from their livers, and yet they have fatty liver disease. These effects were found to be mediated by the peroxisome proliferator-activated receptor alpha (PPARa). Giving riboflavin-deficient mice a compound that increases PPARa activity ameliorated the wasting, low fasting glucose levels, and fatty liver disease. Additional studies on FAD are needed however this study increases our overall scientific knowledge.

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