Ketone body metabolism and sleep homeostasis in mice

Chikahisa, Sachiko; Shimizu, Noriyuki; Shiuchi, Tetsuya; Séi, Hiroyoshi

doi:10.1016/j.neuropharm.2013.12.009

Cited by 33 publications

(25 citation statements)

References 43 publications

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“…Ketone bodies are generated from the breakdown of fatty acids and have been shown to become major fuels in most tissues during starvation, prolonged exercise, or consumption of a high‐fat, low‐carbohydrate diet (Robinson & Williamson, ). Ketogenic diet has been applied as a treatment for epilepsy, autism and brain tumors, and it has been shown to induce sleep alterations (Chikahisa et al., ) possibly by a shift of the excitatory/inhibitory (E/I) balance in the cortex to a more inhibitory state (Boison, ), which is consistent with the lower SWA found in our analysis (Vyazovskiy, Cirelli, Pfister‐Genskow, Faraguna, & Tononi, ). Although less extreme than a pure ketogenic diet, HCD may have an effect on sleep homeostasis through the fatty acids metabolic pathway.…”

Section: Discussionsupporting

confidence: 89%

“…The mechanisms underlying HCD influence on the occurrence of SWA or sleep homeostasis remain elusive. High‐fat feeding and food restriction are thought to enhance ketogenesis (Chikahisa, Shimizu, Shiuchi, & Séi, ). Ketone bodies are generated from the breakdown of fatty acids and have been shown to become major fuels in most tissues during starvation, prolonged exercise, or consumption of a high‐fat, low‐carbohydrate diet (Robinson & Williamson, ).…”

Section: Discussionmentioning

confidence: 99%

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Chronic high‐caloric diet modifies sleep homeostasis in mice

Panagiotou

Meijer

Deboer

2018

Eur J of Neuroscience

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Obesity prevalence and sleep habit changes are commonplace nowadays, due to modern lifestyle. A bidirectional relationship likely exists between sleep quality and metabolic disruptions, which could impact quality of life. In our study, we investigated the effects of a chronic high-caloric diet on sleep architecture and sleep regulation in mice. We studied the effect of 3 months high-caloric diet (HCD, 45% fat) on sleep and the sleep electroencephalogram (EEG) in C57BL/6J mice during 24-hr baseline (BL) recordings, and after 6-hr sleep deprivation (SD). We examined the effect of HCD on sleep homeostasis, by performing parameter estimation analysis and simulations of the sleep homeostatic Process S, a measure of sleep pressure, which is reflected in the non-rapid-eye-movement (NREM) sleep slow-wave-activity (SWA, EEG power density between 0.5 and 4.0 Hz). Compared to controls (n = 11, 30.7 ± 0.8 g), mice fed with HCD (n = 9, 47.6 ± 0.8 g) showed an increased likelihood of consecutive NREM-REM sleep cycles, increased REM sleep and decreased NREM sleep EEG SWA. After SD, these effects were more pronounced. The simulation resulted in a close fit between the time course of SWA and Process S in both groups. HCD fed mice had a slower time constant (T = 15.98 hr) for the increase in homeostatic sleep pressure compared with controls (5.95 hr) indicating a reduced effect of waking on the increase in sleep pressure. Our results suggest that chronic HCD consumption impacts sleep regulation.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Chronic high‐caloric diet modifies sleep homeostasis in mice

Panagiotou

Meijer

Deboer

2018

Eur J of Neuroscience

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“…In our model, pyruvate carboxylase was not increased at the gene expression level, but its gluconeogenic function was likely increased by the increased hepatic acetyl-CoA content, leading to increased hepatic glucose production. With regard to the increased levels of hepatic 3␤-hydroxybutyric acid, a ketone body, Chikahisa et al (10) suggested that ketone body was associated with sleep/wake regulation in the brain. However, the effects of changes in hepatic ketone bodies on brain sleep homeostasis or vice versa are not well established.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice

Shigiyama

Kumashiro

Tsuneoka

et al. 2018

American Journal of Physiology-Endocrinology and Metabolism

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Sleep deprivation is associated with increased risk for type 2 diabetes mellitus. However, the underlying mechanisms of sleep deprivation-induced glucose intolerance remain elusive. The aim of this study was to investigate the mechanisms of sleep deprivation-induced glucose intolerance in mice with a special focus on the liver. We established a mouse model of sleep deprivation-induced glucose intolerance using C57BL/6J male mice. A single 6-hr sleep deprivation by the gentle handling method under fasting condition induced glucose intolerance. Hepatic glucose production assessed by pyruvate challenge test was significantly increased, as was hepatic triglyceride content (by 67.9%) in the sleep deprivation group, compared with freely sleeping control mice. Metabolome and microarray analyses were used to evaluate hepatic metabolites and gene expression levels and determine the molecular mechanisms of sleep deprivation-induced hepatic steatosis. Hepatic metabolites, such as acetyl CoA, 3β-hydroxybutyric acid, and certain acylcarnitines were significantly increased in the sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, fasted sleep-deprived mice showed that hepatic gene expression levels of Elovl3, Lpin1, Plin4, Plin5 and Acot1, which are known to play lipogenic roles, were 2.7, 4.5, 3.7, 2.9, and 2.8 times, respectively, those of the fasted sleeping control group, as assessed by quantitative RT-PCR. Sleep deprivation-induced hepatic steatosis and hepatic insulin resistance seem to be mediated through upregulation of hepatic lipogenic enzymes.

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“…It is noteworthy that the 3-hydroxybutyric acid levels were obviously increased in APP/PS1+CUMS mice; it also known as β-hydroxybutyric acid, a component of ketone bodies, and is produced from the β-oxidation of fatty acids before transfer to other tissues for use. Our previous study found that the effect of insulin resistance was enhanced in APP/PS1+CUMS mice, suggesting a dysfunction of glucose metabolism and bioenergetics in the brain; therefore, the notion that ketone body metabolism may serve as a compensatory pathway for deficits in bioenergetics was suggested, which has been confirmed in sleep-deprivation, stress, and starvation [44, 45]. Nevertheless, research investigating the utilization of ketones is limited in AD; one study indicated a modest increase in SCOT expression (catabolizes ketone bodies into Acetyl-CoA and generates ATP), while the expression of HADHA and SCHAD (enzymes involved in fatty acid oxidation and ketogenesis) was significantly increased 3x in TgAD brain [46].…”

Section: Discussionmentioning

confidence: 99%

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

Han

Wang

Geng³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Stress response is determined by the brain, and the brain is a sensitive target for stress. Our previous experiments have confirmed that once the stress response is beyond the tolerable limit of the brain, particularly that of the hippocampus, it will have deleterious effects on hippocampal structure and function; however, the metabolic mechanisms for this are not well understood. Methods: Here, we used morris water maze, elisa and gas chromatography-time of flight/mass spectrometry to observe the changes in cognition, neuropathology and metabolomics in the hippocampus of APP/PS1 mice and wild-type (C57) mice caused by chronic unpredictable mild stress (CUMS), we also further explored the correlation between cognition and metabolomics. Results: We found that 4 weeks of CUMS aggravated cognitive impairment and increased amyloid-β deposition in APP/PS1 mice, but did not affect C57 mice. Under non-stress conditions, compared with C57 mice, there were 8 different metabolites in APP/PS1 mice. However, following CUMS, 3 different metabolites were changed compared with untreated C57 mice. Compared to APP/PS1 mice, there were 7 different metabolites in APP/PS1+CUMS mice. Among these alterations, 3-hydroxybutyric acid, valine, serine, beta-alanine and o-phosphorylethanolamine, which are involved in sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism. Conclusion: The results indicate that APP/PS1 mice are more vulnerable to stress than C57 mice, and the metabolic mechanisms of stress-related cognitive impairment in APP/PS1 mice are related to multiple pathways and networks, including sphingolipid metabolism, synthesis and degradation of ketone bodies, and amino acid metabolism.

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Ketone body metabolism and sleep homeostasis in mice

Cited by 33 publications

References 43 publications

Chronic high‐caloric diet modifies sleep homeostasis in mice

Chronic high‐caloric diet modifies sleep homeostasis in mice

Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice

Chronic Stress Contributes to Cognitive Dysfunction and Hippocampal Metabolic Abnormalities in APP/PS1 Mice

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