PFKFB2 Is Pivotal for Metabolic Flexibility and Differential Glucose Utilization

Area of Science:

• Cardiovascular Metabolism
• Mitochondrial Physiology
• Enzyme Regulation

Background:

• Cardiac metabolic flexibility is vital for heart function due to fluctuating nutrient availability.
• The enzyme phosphofructokinase-2/fructose 2,6-bisphosphatase (PFKFB2) regulates cardiac glycolysis.
• Previous studies showed PFKFB2 degradation in diabetic hearts and impacts of cardiac-specific knockout (cKO) on glucose pathways and mitochondrial substrate preference.

Purpose of the Study:

• To define the role of PFKFB2 in cardiac mitochondrial metabolic flexibility.
• To investigate the impact of PFKFB2 loss on the heart's response to acute stress.
• To examine effects on cardiac mitochondrial flexibility and O-GlcNAcylation in cKO mice under fasting or pharmacologic stimulation.

Main Methods:

• Cardiac-specific PFKFB2 knockout (cKO) and control mice were studied in fed and fasted states.
• Mice were subjected to pharmacologic stress (caffeine and epinephrine).
• Evaluations included mitochondrial respiration, metabolomics, and systemic glucose homeostasis.

Main Results:

• cKO mice exhibited impaired mitochondrial metabolic flexibility, affecting glucose oxidation and respiration.
• O-GlcNAcylation was upregulated in cKO hearts in the fed state, normalizing in the fasted state.
• PFKFB2 loss impacted systemic glucose homeostasis during fasting and stress.

Conclusions:

• PFKFB2 is essential for adapting cardiac metabolism between fed and fasted states.
• PFKFB2 plays a key regulatory role in protein O-GlcNAcylation.
• Loss of PFKFB2 influences systemic glucose homeostasis under stress.