Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) 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. While 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 for 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 GLUT4 and most glycolytic enzymes. The upregulation of glycolysis was accompanied by the inhibition of fatty acid beta-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.