Diet-induced ketosis protects against focal cerebral ischemia in mouse

Kui Xu, Lena Ye, Katyayini Sharma, Yongming Jin, Matthew M. Harrison, Tylor Caldwell, Jessica M. Berthiaume, Yu Luo, Joseph C. LaManna, Michelle Puchowicz

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Over the past decade we have consistently shown that ketosis is neuroprotective against ischemic insults in rats. We reported that diet-induced ketotic rats had a significant reduction in infarct volume when subjected to middle cerebral artery occlusion (MCAO), and improved survival and recovery after cardiac arrest and resuscitation. The neuroprotective mechanisms of ketosis (via ketogenic diet; KG) include (i) ketones are alternate energy substrates that can restore energy balance when glucose metabolism is deficient and (ii) ketones modulate cell-signalling pathways that are cytoprotective. We investigated the effects of diet-induced ketosis following transient focal cerebral ischemia in mice. The correlation between levels of ketosis and hypoxic inducible factor-1alpha (HIF-1α), AKT (also known as protein kinase B or PKB) and 5′ AMP-activated protein kinase (AMPK) were determined. Mice were fed with KG diet or standard lab-chow (STD) diet for 4 weeks. For the MCAO group, mice underwent 60 min of MCAO and total brain infarct volumes were evaluated 48 h after reperfusion. In a separate group of mice, brain tissue metabolites, levels of HIF-1α, phosphory-lated AKT (pAKT), and AMPK were measured. After feeding a KG diet, levels of blood ketone bodies (beta-hydroxyburyrate, BHB) were increased. There was a proportional decrease in infarct volumes with increased blood BHB levels (KG vs STD; 4.2 ± 0.6 vs 7.8 ± 2.2 mm3, mean ± SEM). A positive correlation was also observed with HIF-1α and pAKT relative to blood BHB levels. Our results showed that chronic ketosis can be induced in mice by KG diet and was neuroprotective against focal cerebral ischemia in a concentration dependent manner. Potential mechanisms include upregulation of cytoprotective pathways such as those associated with HIF-1α, pAKT and AMPK.

Original languageEnglish (US)
Pages (from-to)205-213
Number of pages9
JournalAdvances in experimental medicine and biology
Volume977
DOIs
StatePublished - Jan 1 2017

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Ketosis
Nutrition
Brain Ischemia
Diet
AMP-Activated Protein Kinases
Middle Cerebral Artery Infarction
Sexually Transmitted Diseases
Blood
Ketones
Rats
Brain
Ketogenic Diet
Ketone Bodies
Proto-Oncogene Proteins c-akt
Resuscitation
Cell signaling
Transient Ischemic Attack
Heart Arrest
Reperfusion
Metabolites

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Diet-induced ketosis protects against focal cerebral ischemia in mouse. / Xu, Kui; Ye, Lena; Sharma, Katyayini; Jin, Yongming; Harrison, Matthew M.; Caldwell, Tylor; Berthiaume, Jessica M.; Luo, Yu; LaManna, Joseph C.; Puchowicz, Michelle.

In: Advances in experimental medicine and biology, Vol. 977, 01.01.2017, p. 205-213.

Research output: Contribution to journalArticle

Xu, K, Ye, L, Sharma, K, Jin, Y, Harrison, MM, Caldwell, T, Berthiaume, JM, Luo, Y, LaManna, JC & Puchowicz, M 2017, 'Diet-induced ketosis protects against focal cerebral ischemia in mouse', Advances in experimental medicine and biology, vol. 977, pp. 205-213. https://doi.org/10.1007/978-3-319-55231-6_28
Xu, Kui ; Ye, Lena ; Sharma, Katyayini ; Jin, Yongming ; Harrison, Matthew M. ; Caldwell, Tylor ; Berthiaume, Jessica M. ; Luo, Yu ; LaManna, Joseph C. ; Puchowicz, Michelle. / Diet-induced ketosis protects against focal cerebral ischemia in mouse. In: Advances in experimental medicine and biology. 2017 ; Vol. 977. pp. 205-213.
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abstract = "Over the past decade we have consistently shown that ketosis is neuroprotective against ischemic insults in rats. We reported that diet-induced ketotic rats had a significant reduction in infarct volume when subjected to middle cerebral artery occlusion (MCAO), and improved survival and recovery after cardiac arrest and resuscitation. The neuroprotective mechanisms of ketosis (via ketogenic diet; KG) include (i) ketones are alternate energy substrates that can restore energy balance when glucose metabolism is deficient and (ii) ketones modulate cell-signalling pathways that are cytoprotective. We investigated the effects of diet-induced ketosis following transient focal cerebral ischemia in mice. The correlation between levels of ketosis and hypoxic inducible factor-1alpha (HIF-1α), AKT (also known as protein kinase B or PKB) and 5′ AMP-activated protein kinase (AMPK) were determined. Mice were fed with KG diet or standard lab-chow (STD) diet for 4 weeks. For the MCAO group, mice underwent 60 min of MCAO and total brain infarct volumes were evaluated 48 h after reperfusion. In a separate group of mice, brain tissue metabolites, levels of HIF-1α, phosphory-lated AKT (pAKT), and AMPK were measured. After feeding a KG diet, levels of blood ketone bodies (beta-hydroxyburyrate, BHB) were increased. There was a proportional decrease in infarct volumes with increased blood BHB levels (KG vs STD; 4.2 ± 0.6 vs 7.8 ± 2.2 mm3, mean ± SEM). A positive correlation was also observed with HIF-1α and pAKT relative to blood BHB levels. Our results showed that chronic ketosis can be induced in mice by KG diet and was neuroprotective against focal cerebral ischemia in a concentration dependent manner. Potential mechanisms include upregulation of cytoprotective pathways such as those associated with HIF-1α, pAKT and AMPK.",
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