Nuclear receptor subfamily 4 group a member 2 induces a Warburg-like effect and promotes phospholipids synthesis in the mouse heart

Myocardial metabolic flexibility is critical to ensuring the heart's capacity to maintain contraction and cellular functions under rapidly evolving environmental conditions. Although it is a tightly regulated process, loss of metabolic flexibility is often regarded as a contributing factor to heart failure. This study aims to determine the effects of the early response transcription factor nuclear receptor subfamily 4 group A member 2 (NR4A2) on cardiac metabolism and the resulting impact on left ventricular function. A multiomics approach combining the analysis of global ventricular gene expression, genome-wide NR4A2 binding, and untargeted metabolomics was used to track the molecular effects of cardiomyocyte-specific NR4A2 activation in male and female mice over time. Doppler echocardiography was performed in parallel to monitor changes in left ventricular function. We found that NR4A2 acts as a direct transcriptional activator of the genes encoding the glucose transporter type 4 and most glycolytic enzymes. The upregulation of glycolysis was accompanied by the inhibition of fatty acid β-oxidation and by activation of glutamine-dependent reductive carboxylation to promote the synthesis of phospholipids. This was further supported by NR4A2-dependent transcriptional regulation of key enzymes in the phosphatidic acid pathway. Rewiring of the Krebs cycle for biosynthetic purposes was followed by a progressive decline in left ventricular contractility. In conclusion, our results expose NR4A2 as a critical component of the cell regulatory machinery governing transcriptional reprogramming of cardiac metabolism under stress. These findings provide a conceptual framework illustrating how an acute adaptive metabolic response may become maladaptive on the long-term.<b>NEW & NOTEWORTHY</b> The plasticity of myocardial metabolism is regulated by a poorly understood network of transcription factors. We show that stress-activated nuclear receptor NR4A2 is a potent transcriptional activator of glycolysis in the mouse heart. Prolonged NR4A2 activation triggers a switch from oxidative to biosynthetic metabolism, accompanied by a progressive decline in left ventricular contractility. These findings provide a conceptual framework illustrating how an acute adaptive metabolic response may become maladaptive in the long-term.