Neonates, ketone bodies

Brain Coordination of the nervous system Glycolysis, amino acid metabolism Glucose, amino acid, ketone bodies (in starvation) Polyunsaturated fatty acids in neonate Lactate ... 

The role of fatty acids as oxidizable fuels for brain metabolism is negligible, but ketone bodies, derived from fatty acid oxidation, can be utilized, particularly in the neonatal period. Diseases of carbohydrate and fatty acid metabolism may affect the brain directly or indirectly [1,10]. 

Fructose-1,6-bisphosphatase deficiency, first describ ed by Baker and Winegrad in 1970, has now been reported in approximately 30 cases. It is more common in women and is inherited as an autosomal recessive disorder. Initial manifestations are not strikingly dissimilar from those of glucose-6-phosphatase deficiency. Neonatal hypoglycemia is a common presenting feature, associated with profound metabolic acidosis, irritability or coma, apneic spells, dyspnea, tachycardia, hypotonia and moderate hepatomegaly. Lactate, alanine, uric acid and ketone bodies are elevated in the blood and urine [11]. The enzyme is deficient in liver, kidney, jejunum and leukocytes. Muscle fructose-1,6-bisphosphatase activity is normal. 

Bougneres, P. R, Lemmeil, C., Ferre, P, and Bier, D. M. (1986). Ketone body transport in the human neonate and infant. /. Clin. Invest. Tl, 42-48. 

Nehlig, A. and Pereira de Vasconcelos, A, (1993) Glucose and ketone body utilization by the brain of neonatal rats. Progress in Neurobiology. 40. 163-221. 

The ability to maintain glucose homeostasis during the first few days of life also depends on the activation of gluconeogenesis and the mobilization of fatty acids. Fatty acid oxidation in the liver not only promotes gluconeogenesis (see Chapter 31) but generates ketone bodies. The neonatal brain has an enhanced capacity to use ketone bodies relative to that of infants (fourfold) and adults (40-fold). This ability is consistent with the relatively high fat content of breast milk. 

Monocarboxylic acids, including L-lactate, acetate, pyruvate, and the ketone bodies acetoacetate and (3-hydroxybutyrate, are transported by a separate stere-ospecific system that is slower than the transport system for glucose. During starvation, when the level of ketone bodies in the blood is elevated, this transporter is upregulated. Ketone bodies are important fuels for the brain of both the adult and the neonate during prolonged starvation (greater than 48 hours). 

Bate, A.J. Dickson, A.J. (1986). The importance of ketone bodies as tissue specific fuels in the development of the chick embryo neonate. Biochem. Soc. Trans., 14, 712-13. Bateson, W. (1894). Materials for the Study of Variation. London ... 

One of the functions of hepatic P-oxidation is to provide ketone bodies, acetoac-etate and p-hydroxybutyrate, to the peripheral circulation. These can then be utilized by peripheral tissues such as brain and heart. Beta-oxidation itself produces acetyl-CoA which then has three possible fates entry to the Krebs cycle via citrate S5mthase keto-genesis or transesterification to acetyl-carnitine by the action of carnitine acetyltrans-ferase (CAT). Intramitochondrial acetyl-carnitine then equilibrates with plasma via the carnitine acyl-camitine translocase and presumably via the plasma membrane carnitine transporter. Human studies have shown that acetyl-carnitine may provide up to 5% of the circulating carbon product from fatty acids and can be taker and utilized by muscle and possibly brain." In addition, acyl-camitines are of important with regard to the diagnosis of inborn errors of P- oxidation. For these reasons, we wished to examine the production of acetyl-carnitine and other acyl-camitine esters by neonatal rat hepatocytes. 

There is, however, an immediate and substantial postnatal requirement for ketone bodies by the human neonate, whieh initiates the rapid development and onset of fatty acid p-oxidation, ketogenesis and glueoneogenesis, to meet the energy demands during the first few days after birth. We have hypothesized that these processes would be accompanied by the induetion/aetivation of the ketogenie enzymes such as mHMG-CoA synthase. 

Ketone bodies provide important alternative fuels to body tissues when carbohydrate is in short supply or cannot be efficiently utilized. A particular example is the central nervous systems which cannot utilize plasma fatty acids for energy. Thus in prolonged starvation, ketone bodies become more important than glusose as a fuel source. The possibility of the utilization of ketone bodies obviates the harmful degradation of muscle protein for gluconeogenesis. In addition, acetoacetate and 3-hydroxybutyrate are thought to be important precursors for lipid synthesis in neonatal brain (Webber and Edmond, 1979). 

The concept of "physiological ketosis", the sensitivity of the concentration of ketone bodies in blood to changes in the hormonal and nutritional state (particularly in the neonatal period), and the existence of rapid and specific methods for the estimation of ketone bodies (Williamson et al., 1962) suggest that a request for determination of blood ketone bodies should become a common part of our clinical practice. 

In view of these findings it is felt that careful consideration should be given to further investigation of the use of fat emulsions or ketone body containing fluids in the neonatal period during prolonged surgical procedures, and post-operatively. 

The utilization of ketone bodies by the brain is not limited to the neonatal period Smith et reported a six-fold increase of the activity of 3-hydroxybutyrate dehydrogenase in rat brain in starvation. Unlike the hyperketonaemia of starvation, the hyper-ketonaemia of suckling is accompanied by normal blood glucose concentrations and it is thus possible that in the brain the ketone bodies serve another function (i.e. myeliniza-tion) apart from serving as a fuel for respiration and the sparing of glucose. 

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