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

Authors
 Young-Suk Choi  ;  Jae Eun Song  ;  Jong Eun Lee  ;  Eosu Kim  ;  Chul Hoon Kim  ;  Dong-Hyun Kim  ;  Ho-Taek Song 
Citation
 MOLECULAR BRAIN, Vol.12(1) : 88, 2019 
Journal Title
MOLECULAR BRAIN
Issue Date
2019
Keywords
ATP citrate lyase ; Brain metabolism ; Diabetes ; Hyperpolarized 13C ; Magnetic resonance spectroscopy ; Pyruvate metabolism
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.
Files in This Item:
T201904558.pdf Download
DOI
10.1186/s13041-019-0505-9
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Psychiatry (정신과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eosu(김어수) ORCID logo https://orcid.org/0000-0001-9472-9465
Kim, Chul Hoon(김철훈) ORCID logo https://orcid.org/0000-0002-7360-429X
Song, Ho Taek(송호택) ORCID logo https://orcid.org/0000-0002-6655-2575
Lee, Jong Eun(이종은) ORCID logo https://orcid.org/0000-0001-6203-7413
Choi, Young Suk(최영숙) ORCID logo https://orcid.org/0000-0003-4930-8455
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/173381
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