Hyperpolarized [1-13C]lactate flux increased in the hippocampal region in diabetic mice

Abstract Increasing evidence suggests there is a relationship between cognitive impairment and metabolic dysfunction. Diabetes is a chronic disease, and metabolic factors affecting brain metabolisms, such as serum glucose, insulin, and glucagon, are altered according to disease progression. In our previous study, we applied hyperpolarized [1-13C] pyruvate magnetic resonance spectroscopy in prediabetic mice after feeding them a 60% high-fat diet (HFD) for 6 months. Ultimately, we detected significantly increased [1-13C]lactate conversion in the whole brain and an almost five-fold increased [1-13C]lactate/pyruvate ratio in the hippocampal region. In the present study, we induced diabetes in mice by injecting streptozotocin and feeding them an HFD for 6 months. Unlike in prediabetic mice, [1-13C]lactate conversion in the diabetic mice did not differ from that in the control group, but [1-13C]lactate/total 13C ratio showed an almost 1.4-fold increase in the hippocampal region. We measured the amount of the lactate and mRNA levels of glucose transporters from isolated hippocampus and cortex samples. In the hippocampus, significantly decreased GLUT1 mRNA levels and increased lactate were detected, suggesting an inconsistency between glucose and pyruvate metabolism. Pyruvate can be produced from oxaloacetate as well as glucose. We investigated ATP citrate lyase (ACLY) because it cleaves citrate into oxaloacetate and acetyl CoA. Phosphorylated ACLY (Ser455), the active form, was increased in both hippocampus and cortex samples of mice injected with streptozotocin and fed an HFD. Also, phosphorylated ACLY/total ACLY showed a positive correlation with lactate amount in the hippocampus. Our results suggest that the brain has different responses to diabetic progression, but, in the hippocampus, maintains metabolic alteration toward increasing lactate production from the prediabetic to the diabetic stage. We suggest that ACLY-mediated pyruvate be used to support lactate levels in the hippocampus in cases of limited glucose availability.