ArticleJournal of the American Heart Association2025
PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization.
Article in Journal of the American Heart Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Diet-Associated Regulation of Cardiac Metabolism: Molecular Determinants and Pathophysiological Consequences.Nutrients · 2026Review
- Orchestrating glucose metabolism: PFKFB2 as a signal-integrating conductor in homeostasis and disease.The Journal of biological chemistry · 2026Review
- Triphenylphosphonium compounds preferentially inhibit long-chain fatty acid oxidation in cardiac mitochondria.Research square · 2026Article
- Loss of calcium-dependent phospholipase A2 contributes to multi-omic changes in mouse denervated skeletal muscle.Physiological reports · 2026Article
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6 authors.
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Abstract
backgroundThe heart's constant energy demands make metabolic flexibility critical to its function as nutrient availability varies. The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) contributes to this flexibility by acting as a positive or negative regulator of cardiac glycolysis. We have previously shown that PFKFB2 is degraded in the diabetic heart and that a cardiac-specific PFKFB2 knockout (cKO) impacts ancillary glucose pathways and mitochondrial substrate preference. Therefore, defining PFKFB2's role in mitochondrial metabolic flexibility is paramount to understanding both metabolic homeostasis and metabolic syndromes. Further, it is unknown how PFKFB2 loss impacts the heart's response to acute stress. Here, we examined how cardiac mitochondrial flexibility and the posttranslational modification O-GlcNAcylation are affected in cKO mice in response to fasting or pharmacologic stimulation.
methodscKO and litter-matched controls were euthanized in the fed or fasted (12 hours) states, with or without a 20-minute stimulant stress of caffeine and epinephrine. Mitochondrial respiration, metabolomics, and changes to systemic glucose homeostasis were evaluated.
resultscKO mice had moderate impairment in mitochondrial metabolic flexibility, affecting downstream glucose oxidation, respiration, and carnitine palmitoyl transferase 1 activity. O-GlcNAcylation, a product of ancillary glucose metabolism, was upregulated in cKO hearts in the fed state, but this was ameliorated in the fasted state. Furthermore, metabolic remodeling in response to PFKFB2 loss was sufficient to impact circulating glucose in fasted and stressed states.
conclusionsPFKFB2 is essential for fed-to-fasted changes in cardiac metabolism and plays an important regulatory role in protein O-GlcNAcylation. Its loss also affects systemic glucose homeostasis under stressed conditions.
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