Fatty Acid Oxidation Decreases Independently Of Up-regulated Glucose Utilization In The Setting Of Elevated Afterload

Background: To support the unremitting contractile function of the heart, free fatty acids (FFA) are the substrate of choice, with a shift toward greater reliance on glucose when increased cardiac output is required. However, in the setting of obesity or diabetes, this metabolic flexibility is impaired. The putative necessity of a shift in substrate utilization has been hypothesized to occur due to the lower oxygen requirement of glucose versus fat metabolism, but this has never been tested conclusively. Furthermore, in the case of increased afterload, whereas oxygen demand increases, myocardial oxygen availability remains adequate for fatty acid oxidation (FAO). Therefore, a “preference” for glucose has been proposed. Methods and Results: Pyruvate dehydrogenase complex (PDC) is the rate-limiting enzyme linking glycolysis to the TCA cycle. By over-expressing PDC kinase 4 (PDK4) in cardiomyocytes, we ensured that PDC was phosphorylated and thereby inhibited. This leads to diminished use of pyruvate, limiting energy production primarily to FAO. Unlike high fat diet feeding, which also increases PDK4 and inhibits PDH, this model positioned us to query the impact of PDH inhibition under elevated workload demand in the absence of systemic high fat conditions. As expected, PDK4 transgenic mice manifested normal cardiac output at baseline. However, they manifested a rapid and severe decline in contractile function when challenged with increased afterload triggered by either L-NAME or surgical transverse aortic constriction (TAC). Metabolic flux analysis revealed that, after TAC, fractional FAO decreased - surprisingly - independent of an increase in glucose/pyruvate utilization. Additionally, proteins involved in the transport and oxidation of FFA were paradoxically down-regulated after TAC regardless of genotype. Conclusions: These data demonstrate that cardiomyocytes in a setting in which glucose utilization is clamped and prevented from increasing do not compensate for the deficit in glucose utilization by up-regulating FFA use. In aggregate, our findings suggest that reliance on glucose in the setting of pathological cardiac stress is largely a necessity rather than a simple preference.