Differential metabolic alterations in cortical cell types by feeding a ketogenic diet
by Tim Düking
Date of Examination:2019-06-25
Date of issue:2020-06-18
Advisor:Dr. Gesine Saher
Referee:Prof. Dr. Michael Müller
Referee:Prof. Dr. Tiago Fleming Outeiro
Persistent Address:
http://dx.doi.org/10.53846/goediss-7992
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Abstract
English
The suckling period of rodents is accompanied by marked ketosis as a result of the high fat content of maternal milk. During this time, ketone bodies are the major source of energy for the brain. After weaning when the diet is mainly composed of carbohydrates, glucose becomes the major fuel for the brain. Here we could show that rearing mice on a ketogenic diet (KD) prolongs the metabolic state of ketosis in the brain seen during suckling. Reduced blood glucose concentration and increased ß-hydroxybutyrate levels are characteristic for KD fed animals, thereby reflecting the metabolic situation of the neonatal period. Inducing altered substrate availability by KD resulted in increased expression of monocarboxylate transporter 1 (MCT1) in cortical tissue as well as increased abundance of the key ketolytic enzyme Succinyl-CoA:3-oxoacid-CoA transferase (SCOT). However, detailed mechanistical insight in vivo is lacking and studies did not take into account cell type specific adaptations. We therefore established a refined protocol of MACS-technology, enabling isolation of highly pure cell fractions from individual cortices of adult animals. By using proteomic or transcriptomic analysis of astrocytes, oligodendrocytes, endothelial cells and neurons, cell type specific metabolic adaptations in response to KD feeding were analyzed. Surprisingly, our data indicate that endothelial cells under ketosis support brain metabolism through transport of ketone bodies while they rely on glycolysis. In contrast, astrocytes shifted their metabolism from glucose utilization to ketolysis and ß-oxidation thereby probably sparing glucose for neurons. Of note, oligodendrocytes largely remain metabolically unaltered and seem to support neuronal activity enhanced potassium buffering and potentially transport of ketone bodies. Interestingly, in addition to increased ketolysis neurons upregulated glycolytic enzymes. We speculate that increased utilization of KB and glucose leads to enhanced mitochondrial respiration. In turn, we hypothesize that enhanced mitochondrial respiration might support increased synaptic transmission in neurons and motor activity observed in KD fed mice. Taken together, our data highlight the compartmentalization of brain metabolism in different cell types under ketogenic conditions. Furthermore, these findings might build the basis to understand therapeutical effects of the KD on cellular level in vivo and underscore the need for future cell specific investigations.
Keywords: Ketogenic Diet; Mouse; Brain Metabolism; Astrocytes; Oligodendrocytes; Neurons