Brain Metabolism during Fasting*

Owen, Oliver E.; Morgan, Alfred P.; Kemp, H. G.; Sullivan, James M.; Herrera, M G; Cahill, George F.

doi:10.1172/jci105650

Cited by 1,487 publications

(788 citation statements)

References 22 publications

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“…Increased levels of FFA activate the production of ketone bodies (b-OHB and acetoacetate) by the liver (Felig, 1979). Ketone bodies partially replace glucose as the brain's main source of energy, and enable the adaptive conservation of body protein (Owen et al, 1967;Goodman et al, 1980;Groscolas, 1986). Decreased levels of fT 3 are also reported to limit the breakdown of muscle protein (Gardner et al, 1979).…”

Section: Discussionmentioning

confidence: 99%

Hormones and metabolites of arctic foxes (Alopex lagopus) in response to season, starvation and re-feeding

Fuglei

Aanestad

Berg

2000

Comparative Biochemistry and Physiology Part A: Molecular &

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Svalbard's arctic foxes experience large seasonal variations in light, temperature and food supply throughout the year, which may result in periods of starvation. The aim of this work is to investigate if there are seasonal variations in post-absorptive plasma thyroid hormones (free thyroxin (fT 4 ), free triiodothyronine (fT 3 ) and reverse triiodothyronine (rT 3 )) and metabolites (free fatty-acids (FFA) and b-hydroxybutyrate (b-OHB)) with season and their response to starvation and re-feeding. The concentrations of post-absorptive free triiodothyronine were significantly higher in November than May, while those of thyroxin, reverse triiodothyronine, free fatty-acids and b-hydroxybutyrate remained unchanged. Possible explanations for the seasonal variations in free triiodothyronine are discussed. There were no significant changes from post-absorptive concentrations of thyroxin and reverse triiodothyronine in starved and re-fed foxes. However, free triiodothyronine concentrations decreased during starvation and increased again with re-feeding both in May and November. Starvation induced high levels of free fatty acids in both May and November, indicating increased lipolysis. There was a significant increase in b-hydroxybutyrate in November only, indicating that arctic foxes are capable of protein conservation during starvation.

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Section: Discussionmentioning

confidence: 99%

Hormones and metabolites of arctic foxes (Alopex lagopus) in response to season, starvation and re-feeding

Fuglei

Aanestad

Berg

2000

Comparative Biochemistry and Physiology Part A: Molecular &

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“…GLUT = glucose transporter; MCT = monocarboxylate transporter; PDH = pyruvate dehydrogenase; SCOT = succinyl-coenzyme A:3-ketoacid CoA transferase ketolytic enzymes such as succinyl-coenzyme A (CoA):3-ketoacid CoA transferase instead of pyruvate dehydrogenase (PDH) to produce acetyl-CoA, which condenses with oxaloacetate and enters the citric acid cycle for energy production [31,62]. Several therapeutic strategies aim to enhance brain bioenergetics through supplementation of ketone bodies, including acetoacetate and β-hydroxybutyrate [64,65], or dietary induction of ketogenesis [56]. However, patient compliance on ketogenic diets is challenging owing to its high fat and low carbohydrate content.…”

Section: Current Strategies Targeting Mitochondria and Bioenergeticsmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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“…In classic studies examining brain metabolism during fasting, Owen et al 28 examined the substrate utilization when obese subjects underwent 5 to 6 weeks of complete starvation. During the starvation period, subjects were restricted to one multivitamin capsule, 17 mEq of NaCl, and 1,500 mL of water per day.…”

Section: Hypometabolism As Therapeutic Targetmentioning

confidence: 99%

“…Cerebral use of metabolic fuels was assessed by catheterization, and it is estimated that under such conditions KB supply about 60% of the brains energy requirements. 28 Why use KB during starvation? The primary sources of de novo synthesized glucose are amino acids.…”

Section: Hypometabolism As Therapeutic Targetmentioning

confidence: 99%

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Ketone Bodies as a Therapeutic for Alzheimer's Disease

Henderson¹

2008

Neurotherapeutics

298

120

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Summary: An early feature of Alzheimer's disease (AD) is region-specific declines in brain glucose metabolism. Unlike other tissues in the body, the brain does not efficiently metabolize fats; hence the adult human brain relies almost exclusively on glucose as an energy substrate. Therefore, inhibition of glucose metabolism can have profound effects on brain function. The hypometabolism seen in AD has recently attracted attention as a possible target for intervention in the disease process. One promising approach is to supplement the normal glucose supply of the brain with ketone bodies (KB), which include acetoacetate, ␤-hydroxybutyrate, and acetone. KB are normally produced from fat stores when glucose supplies are limited, such as during prolonged fasting. KB have been induced both by direct infusion and by the administration of a high-fat, low-carbohydrate, low-protein, ketogenic diets. Both approaches have demonstrated efficacy in animal models of neurodegenerative disorders and in human clinical trials, including AD trials. Much of the benefit of KB can be attributed to their ability to increase mitochondrial efficiency and supplement the brain's normal reliance on glucose. Research into the therapeutic potential of KB and ketosis represents a promising new area of AD research.

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Brain Metabolism during Fasting*

Cited by 1,487 publications

References 22 publications

Hormones and metabolites of arctic foxes (Alopex lagopus) in response to season, starvation and re-feeding

Hormones and metabolites of arctic foxes (Alopex lagopus) in response to season, starvation and re-feeding

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

Ketone Bodies as a Therapeutic for Alzheimer's Disease

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