Adaptation to Chronic Hypoxia During Diet-Induced Ketosis

Puchowicz, Michelle A.; Emancipator, Douglas; Xu, Kui; Magness, Danielle L.; Ndubuizu, Obinna I.; Lust, W. David; LaManna, Joseph Charles

doi:10.1007/0-387-26206-7_8

Cited by 22 publications

(15 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Plasma samples from rats used for the ␤-HB influx and blood flow experiments were analyzed for glucose, lactate, and ketones (␤-HB) by standard enzymatic assays on a Cobas Faras centrifuge analyzer-spectrophotometry system (Roche). In the rats used for immunohistochemical and immunocytochemical analyses, a small blood sample taken by tail stick from the KG group at week 3 and on the final day just before collection of brain tissue was tested using a MediSense Precision Xtra ketone meter (Abbott Laboratories, Bedford, MA) to ensure blood ketosis (␤-HB) levels Ͼ1.0 mM (33).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Diet-induced ketosis increases capillary density without altered blood flow in rat brain

Puchowicz¹,

Xu²,

Sun³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

Puchowicz MA, Xu K, Sun X, Ivy A, Emancipator D, LaManna JC. Diet-induced ketosis increases capillary density without altered blood flow in rat brain. Am J Physiol Endocrinol Metab 292: E1607-E1615, 2007. First published February 6, 2007; doi:10.1152/ajpendo.00512.2006.-It is recognized that ketone bodies, such as R-␤-hydroxybutyrate (␤-HB) and acetoacetate, are energy sources for the brain. As with glucose metabolism, monocarboxylate uptake by the brain is dependent on the function and regulation of its own transporter system. We concurrently investigated ketone body influx, blood flow, and regulation of monocarboxylate transporter (MCT-1) and glucose transporter (GLUT-1) in diet-induced ketotic (KG) rat brain. Regional blood-to-brain ␤-HB influx (mol⅐g Ϫ1 ⅐min Ϫ1) increased 40-fold with ketosis (4.8 Ϯ 1.8 plasma␤-HB; mM) in all regions compared with the nonketotic groups (standard and no-fat diets); there were no changes in regional blood flow. Immunohistochemical staining revealed that GLUT-1 density (number/mm 2 ) in the cortex was significantly elevated (40%) in the ketotic group compared with the standard and no-fat diet groups. MCT-1 was also markedly (3-fold) upregulated in the ketotic group compared with the standard diet group. In the standard diet group, 40% of the brain capillaries stained positive for MCT-1; this amount doubled with the ketotic diet. Western blot analysis of isolated microvessels from ketotic rat brain showed an eightfold increase in GLUT-1 and a threefold increase in MCT-1 compared with the standard diet group. These data suggest that diet-induced ketosis results in increased vascular density at the blood-brain barrier without changes in blood flow. The increase in extraction fraction and capillary density with increased plasma ketone bodies indicates a significant flux of substrates available for brain energy metabolism. ketone bodies; monocarboxylate transporter-1; GLUT-1; ␤-hydroxybutyrate; brain metabolism; blood-brain barrier GLUCOSE IS THE MAJOR METABOLIC FUEL for the mammalian brain (37, 41), but alternate energy substrates such as ketone bodies, e.g., R-␤-hydroxybutyrate (␤-HB) and acetoacetate (6,19,29,39), serve as efficient metabolic fuel sources for the brain. This is especially important under certain nutritional conditions, such as fasting, starvation (28), feeding of a high-fat diet (24, 26), and early development and throughout the suckling period (2, 25, 42). Clinicians and investigators have been interested in ketone bodies as therapeutic agents for the treatment of hypoglycemia, seizure disorders, and Alzheimer's and Parkinson's diseases and as alternatives to high-lipid parenteral and enteral feedings (5,14,43).Similar in chemical structure to lactate and pyruvate (intermediates of glycolysis), ketones are metabolized by the brain, especially neonatal mammalian brain (1,2,20,40). These short-chain acids are referred to as monocarboxylates, and, as with glucose metabolism, systemic delivery of these substrates and availability for neuronal uptake are highly depe...

show abstract

Section: Methodsmentioning

confidence: 99%

“…Subsequent work in rats led to a modified uptake method, known as the single-pass dual-label isotope-indicator (unidirectional tracer) method, which allows for quantitation of substrates, such as glucose, lactate, or ketones, at the endothelial boundary of the BBB, as well as simultaneous estimation of blood flow (7,16,33).…”

mentioning

confidence: 99%

Diet-induced ketosis increases capillary density without altered blood flow in rat brain

Puchowicz¹,

Xu²,

Sun³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…High tolerance to hypoxia has been associated with increased plasma ketone levels (Eiger et al, 1980;D'Alecy et al, 1990). The use of the ketogenic diet for 3 weeks has shown to increase tolerance to in vivo hypoxia (Puchowicz et al, 2005). Administration of 4 mmol/L b-OHB to hypoxic hippocampal neurons decreased acute cell death, decreased the number of apoptotic Cerebral metabolic adaptation and ketone metabolism after brain injury ML Prins cells, maintained mitochondrial membrane potential, and decreased caspase-3 activation and poly-ADP-ribose polymerase cleavage (Masuda et al, 2005).…”

Section: Prinsmentioning

confidence: 99%

Cerebral Metabolic Adaptation and Ketone Metabolism after Brain Injury

Prins¹

2007

J Cereb Blood Flow Metab

211

184

View full text Add to dashboard Cite

The developing central nervous system has the capacity to metabolize ketone bodies. It was once accepted that on weaning, the 'post-weaned/adult' brain was limited solely to glucose metabolism. However, increasing evidence from conditions of inadequate glucose availability or increased energy demands has shown that the adult brain is not static in its fuel options. The objective of this review is to summarize the body of literature specifically regarding cerebral ketone metabolism at different ages, under conditions of starvation and after various pathologic conditions. The evidence presented supports the following findings: (1) there is an inverse relationship between age and the brain's capacity for ketone metabolism that continues well after weaning; (2) neuroprotective potentials of ketone administration have been shown for neurodegenerative conditions, epilepsy, hypoxia/ischemia, and traumatic brain injury; and (3) there is an age-related therapeutic potential for ketone as an alternative substrate. The concept of cerebral metabolic adaptation under various physiologic and pathologic conditions is not new, but it has taken the contribution of numerous studies over many years to break the previously accepted dogma of cerebral metabolism. Our emerging understanding of cerebral metabolism is far more complex than could have been imagined. It is clear that in addition to glucose, other substrates must be considered along with fuel interactions, metabolic challenges, and cerebral maturation.

show abstract

“…7 illustrates the relationship between brain cancer management and circulating levels of glucose and ketones. Elevated ketones will reduce glycolysis especially when circulating glucose levels are reduced (Kashiwaya et al, 1994(Kashiwaya et al, , 2010Katayama et al, 1994;Puchowicz et al, 2005). Tumor cells have a greater Figure 7 Relationship of circulating levels of glucose and ketones (␤-hydroxybutyrate, ␤-OHB) to brain tumor management.…”

Section: Dietary Caloric Adjustments and Brain Cancer Managementmentioning

confidence: 99%

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

et al. 2012

View full text Add to dashboard Cite

Summary Malignant brain cancer persists as a major disease of morbidity and mortality. The failure to recognize brain cancer as a disease of energy metabolism has contributed in large part to the failure in management. As long as brain tumor cells have access to glucose and glutamine, the disease will progress. The current standard of care provides brain tumors with access to glucose and glutamine. The high fat low carbohydrate ketogenic diet (KD) will target glucose availability and possibly that of glutamine when administered in carefully restricted amounts to reduce total caloric intake and circulating levels of glucose. The restricted KD (RKD) targets major signaling pathways associated with glucose and glutamine metabolism including the IGF-1/PI3K/Akt/Hif pathway. The RKD is anti-angiogenic, anti-invasive, anti-inflammatory, and pro-apoptotic when evaluated in mice with malignant brain cancer. The therapeutic efficacy of the restricted KD can be enhanced when combined with drugs that also target glucose and glutamine. Therapeutic efficacy of the RKD was also seen against malignant gliomas in human case reports. Hence, the RKD can be an effective non-toxic therapeutic option to the current standard of care for inhibiting the growth and invasive properties of malignant brain cancer. © 2011 Elsevier B.V. All rights reserved. Ketogenic diet and epilepsy managementThe high fat, low carbohydrate ketogenic diet (KD) has long been recognized as an effective non-toxic therapy for managing epileptic seizures in children (Freeman and Kossoff, 2010). The mechanisms by which the KD manages seizures are linked to shifts in brain energy metabolism (DeVivo 0920-1211/$ -see front matter

show abstract

Adaptation to Chronic Hypoxia During Diet-Induced Ketosis

Cited by 22 publications

References 13 publications

Diet-induced ketosis increases capillary density without altered blood flow in rat brain

Diet-induced ketosis increases capillary density without altered blood flow in rat brain

Cerebral Metabolic Adaptation and Ketone Metabolism after Brain Injury

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

Contact Info

Product

Resources

About