Vitamin B2 Enables Regulation of Fasting Glucose Availability

Authors

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

Publication Date

7-7-2023

Journal

ELife

DOI

10.7554/eLife.84077

PMID

37417957

PMCID

PMC10328530

PubMedCentral® Posted Date

7-7-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Animals, Glucose, PPAR alpha, Flavin-Adenine Dinucleotide, Fatty Acids, Liver, Fasting, Non-alcoholic Fatty Liver Disease, Oxidation-Reduction, Flavoproteins

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 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.

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