Abstract Thu090: Glucocorticoids activate cardiac ketolysis across heart failure contexts through the clock factor RORα

In mice and humans, ketone bodies are a critical fuel to alleviate the energy deficit in the failing heart, but it is still unknown whether and which is the common mechanism activating ketolysis across diverse heart failure types. Glucocorticoid steroids are pleiotropic stress signals that regulate energy metabolism in the heart, but their role in cardiac ketolysis is completely unknown. Using cardiomyocyte-specific inducible GR knockout (KO) mice and 13C tracing from labeled beta-hydroxybutyrate, we found that glucocorticoids directly transactivate beta-hydroxybutyrate dehydrogenase 1 (BDH1) expression in heart and activate cardiac ketolysis in a GR-dependent manner. The human relevance of this finding was confirmed at transcriptional and metabolic levels by evidence from human pediatric myocardial biopsies and hiPSC-derived cardiomyocytes. Furthermore through IP-MS and ChIP-seq/RNA-seq datasets, we identified the clock factor RORα as a novel GR interactor and transactivation target, non-redundantly required for Bdh1 activation by glucocorticoids. Inducible cardiomyocyte-specific RORα-KO mice revealed that RORα is required for Bdh1 activation and cardiac ketolysis in the systolic cardiomyopathy induced by transverse aortic constriction coupled to myocardial infarction (TAC+MI). In both type-1 and -2 diabetic models, RORα loss exacerbated diastolic dysfunction and hypertrophy, while nobiletin – a direct RORα agonist - rescued ketolysis and function through RORα. These findings highlight the glucocorticoid-clock axis as common activator of cardiac ketolysis across heart failure contexts and suggest RORα as a therapeutic target for improving cardioprotective ketone utilization.