APOΕ4 lowers energy expenditure in females and impairs glucose oxidation by increasing flux through aerobic glycolysis.

Autor: Farmer BC; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Williams HC; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA.; Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA., Devanney NA; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA.; Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA., Piron MA; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Nation GK; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Carter DJ; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Walsh AE; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Khanal R; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Young LEA; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Kluemper JC; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Hernandez G; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Allenger EJ; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Mooney R; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Golden LR; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Smith CT; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Brandon JA; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA., Gupta VA; Gill Heart and Vascular Institute, University of Kentucky, Lexington, KY, USA., Kern PA; Center for Clinical and Translational Science, University of Kentucky College of Medicine, Lexington, KY, USA.; Department of Internal Medicine, Division of Endocrinology, University of Kentucky, Lexington, KY, USA., Gentry MS; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA., Morganti JM; Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA.; Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA., Sun RC; Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA., Johnson LA; Department of Physiology, University of Kentucky College of Medicine, UKMC/MS 609, 800 Rose Street, Lexington, KY, 40536, USA. Johnson.Lance@uky.edu.; Sanders Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA. Johnson.Lance@uky.edu.
Jazyk: angličtina
Zdroj: Molecular neurodegeneration [Mol Neurodegener] 2021 Sep 06; Vol. 16 (1), pp. 62. Date of Electronic Publication: 2021 Sep 06.
DOI: 10.1186/s13024-021-00483-y
Abstrakt: Background: Cerebral glucose hypometabolism is consistently observed in individuals with Alzheimer's disease (AD), as well as in young cognitively normal carriers of the Ε4 allele of Apolipoprotein E (APOE), the strongest genetic predictor of late-onset AD. While this clinical feature has been described for over two decades, the mechanism underlying these changes in cerebral glucose metabolism remains a critical knowledge gap in the field.
Methods: Here, we undertook a multi-omic approach by combining single-cell RNA sequencing (scRNAseq) and stable isotope resolved metabolomics (SIRM) to define a metabolic rewiring across astrocytes, brain tissue, mice, and human subjects expressing APOE4.
Results: Single-cell analysis of brain tissue from mice expressing human APOE revealed E4-associated decreases in genes related to oxidative phosphorylation, particularly in astrocytes. This shift was confirmed on a metabolic level with isotopic tracing of 13 C-glucose in E4 mice and astrocytes, which showed decreased pyruvate entry into the TCA cycle and increased lactate synthesis. Metabolic phenotyping of E4 astrocytes showed elevated glycolytic activity, decreased oxygen consumption, blunted oxidative flexibility, and a lower rate of glucose oxidation in the presence of lactate. Together, these cellular findings suggest an E4-associated increase in aerobic glycolysis (i.e. the Warburg effect). To test whether this phenomenon translated to APOE4 humans, we analyzed the plasma metabolome of young and middle-aged human participants with and without the Ε4 allele, and used indirect calorimetry to measure whole body oxygen consumption and energy expenditure. In line with data from E4-expressing female mice, a subgroup analysis revealed that young female E4 carriers showed a striking decrease in energy expenditure compared to non-carriers. This decrease in energy expenditure was primarily driven by a lower rate of oxygen consumption, and was exaggerated following a dietary glucose challenge. Further, the stunted oxygen consumption was accompanied by markedly increased lactate in the plasma of E4 carriers, and a pathway analysis of the plasma metabolome suggested an increase in aerobic glycolysis.
Conclusions: Together, these results suggest astrocyte, brain and system-level metabolic reprogramming in the presence of APOE4, a 'Warburg like' endophenotype that is observable in young females decades prior to clinically manifest AD.
(© 2021. The Author(s).)
Databáze: MEDLINE
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