Diabetes is an independent risk factor for the development of heart failure. In diabetic hearts, it has been reported that increased fatty acid (FA) uptake and deranged FA use result in accumulation of cardiotoxic lipids and reduced cardiac efficiency that compromise systolic and diastolic function. To date, lipotoxicity hypothesis is prevailing as a key event driving diabetic cardiomyopathy and it is proposed that limited FA use is beneficial for diabetic hearts. However, it has not been fully studied whether limited FA use is actually beneficial in-vivo beating hearts in diabetes. CD36, a transmembrane glycoprotein, has a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport and oxidation with marked enhancement of glucose use. In this study, we explored whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. Contrary to our expectations, we found that cardiac contractile dysfunction was deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake, estimated by 18 F-FDG uptake, was not reduced in CD36KO-STZ hearts, total energy supply, estimated by the pool size of the TCA cycle, was significantly reduced in CD36KO-STZ hearts. Isotopomer analysis with 13 C 6 -glucose revealed that accelerated glycolysis, estimated by enrichment of 13 C 3 -lactate, 13 C 2 -alanine, 13 C 2 -citrate and 13 C 2 -malate, in CD36KO hearts was markedly suppressed by STZ treatment. On the other hand, levels of ceramides, cardiotoxic lipids from excessive FA, were not elevated in CD36KO-STZ hearts compared to WT-STZ. Further, increased energy demand induced by transverse aortic constriction resulted in synergistic exacerbation of cardiac contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis, leading to cardiac contractile dysfunction. Therefore, it is very likely that enhanced FA use in diabetic hearts occurs to compensate for reduced glucose use, and that limitation of FA utilization could be detrimental to the development of diabetic cardiomyopathy.
Read full abstract