Abstract P3050: The Adropin-GPR19 Signaling Axis In Diabetic Cardiomyopathy

Background: Diabetic cardiomyopathy (DCM) is a major complication of diabetes and has been recognized as a cause of heart failure independent of other common risk factors for cardiac disease. In DCM, increased free fatty acid availability and decreased myocardial glucose uptake lead to a reliance on fatty acid oxidation for ATP generation. This loss of metabolic flexibility can reduce cardiac plasticity in response to stress. Energetic inefficiency in diabetic hearts may have profound implications for cardiac function under conditions of increased workload, and therefore therapeutic approaches are warranted. Alleviating metabolic inflexibility, by promoting cardiac glucose utilization, has been proposed as a potential strategy to reverse cardiomyopathy in diabetic and obese patients. Adropin is a liver- and brain-secreted peptide hormone shown to regulate fuel metabolism in a number of tissues, including the heart. Adropin levels are significantly reduced in obese and diabetic human subjects, and this decrease is linked to increased adiposity, insulin resistance, and impaired glucose tolerance. Our lab recently showed that adropin treatment restores glucose oxidation activity in vivo by reducing the expression of the mitochondrial acetyltransferase enzyme GCN5L1. The reduction in GCN5L1 abundance altered the acetylation and activity of fuel metabolism enzymes to favor glucose utilization; however, the mechanism that underlies this effect remains unknown. Our data suggests that the class A orphan G-coupled protein receptor, GPR19, acts as a putative cellular receptor for adropin in cardiac cells to regulate mitochondrial bioenergetic output. Hypothesis: We hypothesize that adropin-GPR19 signaling regulates GCN5L1 expression, which in turn promotes the deacetylation and activity of pyruvate dehydrogenase to restore glucose utilization in the diabetic heart. Methods: We used a novel whole-body GPR19 knockout mouse to perform a preliminary characterization of the effects of GPR19 depletion on cardiac and whole-body physiology. Using in vivo metabolic approaches, we report that GPR19 KO mice exhibit sex-dependent glucose intolerance, and display markers of altered cardiac energy metabolism. Conclusions: These findings further define the fundamental role of the adropin-GPR19 signaling pathway in the regulation of metabolic homeostasis, and thus highlight a potential target for therapeutic interventions in DCM.