The metabolism of ketone bodies in developing human brain: development of ketone‐body‐utilizing enzymes and ketone bodies as precursors for lipid synthesis

Patel, Mulchand S.; Johnson, Clifton; R, Rajan; Owen, Oliver E.

doi:10.1111/j.1471-4159.1975.tb04428.x

Cited by 84 publications

(28 citation statements)

References 31 publications

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“…Mitochondrial enzymes important for the oxidative metabolism of glucose, such as pyruvate dehydrogenase, have relatively lower activities than those from the adult brain [89][90][91] . This coincides with the relatively higher activities of enzymes for ketone bodies utilization [92] . In addition, the developing brain may have a greater ability to utilize lactate as a fuel, especially in the immediate postnatal period [93] .…”

Section: Unique Features Of the Developing Brainmentioning

confidence: 99%

The Potential Role of Mitochondria in Pediatric Traumatic Brain Injury

et al. 2006

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Mitochondria play a central role in cerebral energy metabolism, intracellular calcium homeostasis and reactive oxygen species generation and detoxification. Following traumatic brain injury (TBI), the degree of mitochondrial injury or dysfunction can be an important determinant of cell survival or death. Literature would suggest that brain mitochondria from the developing brain are very different from those from mature animals. Therefore, aspects of developmental differences in the mitochondrial response to TBI can make the immature brain more vulnerable to traumatic injury. This review will focus on four main areas of secondary injury after pediatric TBI, including excitotoxicity, oxidative stress, alterations in energy metabolism and cell death pathways. Specifically, we will describe what is known about developmental differences in mitochondrial function in these areas, in both the normal, physiologic state and the pathologic state after pediatric TBI. The ability to identify and target aspects of mitochondrial dysfunction could lead to novel neuroprotective therapies for infants and children after severe TBI.

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Section: Unique Features Of the Developing Brainmentioning

confidence: 99%

The Potential Role of Mitochondria in Pediatric Traumatic Brain Injury

et al. 2006

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“…Since this capacity is already functional in the immature human brain (6)(7)(8)(9), ketone bodies might play an important role in the caloric homeostasis of newly born infants. Furthermore, AcAc and 3-OHB are important precursors for the synthesis of structural lipids in the developing human brain (10). Whether fasted for the first 24 h of life (11,12) or fed under current nursery practices (3,13), newborn infants have a degree of ketosis that is achieved by the adult only after 1-2 d of total starvation ( 14).…”

Section: Introductionmentioning

confidence: 99%

Ketone body transport in the human neonate and infant.

Bougnères¹,

Lemmel²,

Ferré³

et al. 1986

J. Clin. Invest.

112

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Using a continuous intravenous infusion of D-(-)-3-hydroxyl4,4,4_2H31butyrate tracer, we measured total ketone body transport in 12 infants: six newborns, four 1-6-mo-olds, one diabetic, and one hyperinsulinemic infant. Ketone body inflow-outflow transport (flux) averaged 17.3±1.A Mmol kg-' min' in the neonates, a value not different from that of 20.6±0.9 !mol kg-' min' measured in the older infants. This rate was accelerated to 32.2 jAmol kg-' min' in the diabetic and slowed to 5.0 gsmol kg-' min-' in the hyperinsulinemic child. As in the adult, ketone turnover was directly proportional to free fatty acid and ketone body concentrations, while ketone clearance declined as the circulatory content of ketone bodies increased.Compared with the adult, however, ketone body turnover rates of 12.8-21.9 jsmol kg-' min' in newborns fasted for <8 h, and rates of 17.9-26.0 gsmol kg-' min-' in older infants fasted for <10 h, were in a range found in adults only after several days of total fasting. If the bulk of transported ketone body fuels are oxidized in the infant as they are in the adult, ketone bodies could account for as much as 25% of the neonate's basal energy requirements in the first several days of life. These studies demonstrate active ketogenesis and quantitatively important ketone body fuel transport in the human infant. Furthermore, the qualitatively similar relationships between the newborn and the adult relative to free fatty acid concentration and ketone inflow, and with regard to ketone concentration and clearance rate, suggest that intrahepatic and extrahepatic regulatory systems controlling ketone body metabolism are well established by early postnatal life in humans.

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“…The D-form of ␤-OHB is believed to be the physiologically more important isomer (12, 13), but isoenzymes for the utilization of both the D-and L-isomers of ␤-OHB are expressed from early gestational age in various tissues (24). Because of preliminary data on one patient with a fatty acid oxidation defect treated with DL sodium ␤-OHB (19) and the easier access to the DLracemate, we have decided to administer the DL-form of sodium ␤-OHB to our patients.…”

Section: Discussionmentioning

confidence: 99%

Oral β-Hydroxybutyrate Supplementation in Two Patients with Hyperinsulinemic Hypoglycemia: Monitoring of β-Hydroxybutyrate Levels in Blood and Cerebrospinal Fluid, and in the Brain by In Vivo Magnetic Resonance Spectroscopy

et al. 2002

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In persistent hyperinsulinemic hypoglycemia of infancy, ketone body concentrations are abnormally low at times of hypoglycemia, depriving the brain of its most important alternative fuel. The neuroprotective effect of endogenous ketone bodies is evidenced by animal and human studies, but knowledge about exogenous supply is limited. Assuming that exogenous ketone body compounds as a dietetic food might replace this alternative energy source for the brain, we have monitored the fate of orally supplemented DL sodium ␤-hydroxybutyrate (␤-OHB) in two 6-mo-old infants with persistent hyperinsulinemic hypoglycemia for 5 and 7 mo, while on frequent tube-feedings and treatment with octreotide. Near total (95%) pancreatectomy had been ineffective in one patient and was refused in the other. In blood, concentrations of ␤-OHB increased to levels comparable to a 16-to 24-h fast while on DL sodium ␤-OHB 880 to 1000 mg/kg per day. In cerebrospinal fluid, concentrations of ␤-OHB increased to levels comparable to a 24-to 40-h fast, after single dosages of 4 and 8 g, respectively. High ratios of ␤-OHB to acetoacetate indicated exogenous origin of ␤-OHB. An increase of intracerebral concentrations of ␤-OHB could be demonstrated by repetitive single-voxel proton magnetic resonance spectroscopy by a clear doublet at 1.25 ppm. Oral DL sodium ␤-OHB was tolerated without side effects. This first report on oral supplementation of DL sodium ␤-OHB in two patients with persistent hyperinsulinemic hypoglycemia demonstrates effective uptake across the blood-brain barrier and could provide the basis for further evaluation of the neuroprotective effect of ␤-OHB in conditions with hypoketotic hypoglycemia. PHHI is the most common cause of recurrent hypoglycemia in infancy (1). PHHI is characterized by inappropriately high blood insulin levels in the presence of symptomatic hypoglycemia (2) and by a prompt responsiveness to glucagon (3).Pathogenetically, PHHI may result from different molecular defects in the regulation of ␤-cell-mediated insulin release with diffuse or focal ␤-cell hyperplasia (4, 5).Treatment with diazoxide, a potassium-channel opener at the pancreatic ␤-cell and inhibitor of insulin secretion, and octreotide, a long-acting somatostatin analog, is often hampered by poor effect or severe side effects (3, 6 -9), and pancreatectomy, at least in cases with diffuse hyperplasia, bears the risk of postoperative diabetes (10).In most hypoglycemic states, ketone bodies (␤-OHB and AA) are released from counterregulatory lipolysis, serving as an alternative, neuroprotective, energetic fuel for the brain (3,

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The metabolism of ketone bodies in developing human brain: development of ketone‐body‐utilizing enzymes and ketone bodies as precursors for lipid synthesis

Cited by 84 publications

References 31 publications

The Potential Role of Mitochondria in Pediatric Traumatic Brain Injury

The Potential Role of Mitochondria in Pediatric Traumatic Brain Injury

Ketone body transport in the human neonate and infant.

Oral β-Hydroxybutyrate Supplementation in Two Patients with Hyperinsulinemic Hypoglycemia: Monitoring of β-Hydroxybutyrate Levels in Blood and Cerebrospinal Fluid, and in the Brain by In Vivo Magnetic Resonance Spectroscopy

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