Controle do fornecimento e da utilização de substratos energéticos no encéfalo

Schelp, A.O.; Burini, R.C.

doi:10.1590/S0004-282X1995000400025

Resumos

Correspondendo a apenas 2% do peso corpóreo, o cérebro apresenta taxa metabólica superior à maioria dos demais órgãos e sistemas. A maior parte do consumo energético encefálico ocorre no transporte iônico para manutenção do potencial de membrana celular. Praticamente desprovido de estoques, os substratos energéticos para o encéfalo são fornecidos necessariamente pela circulação sanguínea.O suprimento desses substratos sofre também a ação seletiva da barreira hemato-encefálica (BHE). O principal substrato, que é a glicose, tem uma demanda de 150 g/dia (0,7 mM/g/min). A metabolização intracelular parece ser controlada pela fosfofrutoquinase. A manose e os produtos intermediários do metabolismo (frutose 1,6 bifosfato, piruvato, lactato e acetato) podem substituir, em parte, a glicose, quando os níveis sangüíneos desta encontram-se elevados. Quando oxidado, o lactato chega a responder por 21% do consumo cerebral de Ov Em situações de isquemia e inflamação infecciosa, o tecido cerebral passa de consumidor a produtor de lactato. Os corpos cetônicos também podem reduzir as necessidades cerebrais de glicose desde que oferecidos em quantidades suficientes ao encéfalo. Entretanto, devem ser considerados como um substrato complementar e nunca alternativo da glicose, pois comprometem a produção cerebral de succinil CoA e GTP. Quanto aos demais substratos, embora apresentem condições metabólicas, não existem demonstrações consistentes de que o cérebro produza energia a partir dos ácidos graxos sistêmicos, mesmo em situações de hipoglicemia. De maneira análoga, etanol e glicerol são considerados apenas a nível de experimentação. A utilização dos aminoácidos é dependente da sua captação, limitada tanto pela baixa concentração sangüínea, como pela seletividade da BHE. A maior captação ocorre para os de cadeia ramificada e destes, a valina. A menor captação é a de aminoácidos sintetizados no cérebro (aspartato,gluconato e alanina). Todos podem ser oxidados a CO, e H(2)0. Entretanto, mesmo com o consumo de glicose reduzido a 50%, a contribuição energética dos aminoácidos não ultrapassa 10%. Para manter o suprimento adequado de glicose e oxigênio, o fluxo sangüíneo cerebral é da ordem de 800 ml/min (15% do débito cardíaco). O consumo de O, pelo cérebro é equivalente a 20% do total consumido pelo corpo. Esses mecanismos, descritos como controladores da utilização de substratos energéticos pelo cérebro, sofrem a influência da idade apenas no período perinatal, com a oxidação do lactato na fase pré-latente e dos corpos cetônicos, no início da amamentação.

cérebro; substratos energéticos; metabolismo

Altrough accounting for 2% of body weight, brain has one of the greatest metabolic rates compared with other organs and systems. The energy metabolic consum is expended mainly in the maintenance of ionic gradient, essential to neuronal activity. Brain receives energy substrates from circulation, with interference of blood brain barrier (BBB). Glucose is the main substrate and has a metabolic rate so high as 150 g/day (0,7 mM/G/min). At cellular level, metabolism of glucose seems to be controlled by phosphofructokynase. If the cellular level were high enough, manose and other products like fructose 1,6 biphosphate, pyruvate, lactate and acetate can be used in the place of glucose. Lactate, when oxyded, consums at least 21 % of the cerebral needs of 0,. In ischemia and inflammatory infections, brain tissue produces lactate instead of use it. Ketone bodies reduce cerebral needs of glucose; in view of the disturbances that occur in cerebral production of succinyl CoA and guanosine 3 phosphate (GTP), they must be considered as complementary substrate but not as an alternative one. Although they can be metabolized, there are no evidences that brain could produce energy from systemic free fatty acids, even when hypoglicemia is present. Ethanol and glycerol are considered only at experimental level. Brain uptake of aminoacids occur better for long chain aminoacids, specially valine. The aminoacids that are synthetised in the brain (aspartate,gluconate and alanine) show the lower absortion rates. All aminoacids should be oxided to CO, and H,0. Even when glucose consum is reduced to 30%, aminoacid accounts for only 10% of the energetic expenditure of the brain. To maintain cerebral glucose and oxygen supply to the brain , blood flow must be at least 800 ml/min. The regulation of supply and consumption of energy substrate by the brain is changed in few situations. Among them, are included the oxidation of lactate immediately before milk diet early in development and utilization of ketone bodies at the beginning of lactation. This review includes a brief discussion about the relevance of glucose as the main energy substrate for cerebral tissue in different ages and ischemia or hypoxia.

brain; energy substrate; metabolism

Controle do fornecimento e da utilização de substratos energéticos no encéfalo

Modulation of energy substrate supply and consumption by the brain

A.O. Schelp^I; R.C. Burini^II

^IMédico, pós-graduando do curso de Patologia. Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP)

^IIProfessor Titular Departamento de Clínica Médica, Chefe do Laboratório de Bioquímica Nutricional e Metabólica. Faculdade de Medicina de Botucatu da Universidade Estadual Paulista (UNESP)

RESUMO

Correspondendo a apenas 2% do peso corpóreo, o cérebro apresenta taxa metabólica superior à maioria dos demais órgãos e sistemas. A maior parte do consumo energético encefálico ocorre no transporte iônico para manutenção do potencial de membrana celular. Praticamente desprovido de estoques, os substratos energéticos para o encéfalo são fornecidos necessariamente pela circulação sanguínea.O suprimento desses substratos sofre também a ação seletiva da barreira hemato-encefálica (BHE). O principal substrato, que é a glicose, tem uma demanda de 150 g/dia (0,7 mM/g/min). A metabolização intracelular parece ser controlada pela fosfofrutoquinase. A manose e os produtos intermediários do metabolismo (frutose 1,6 bifosfato, piruvato, lactato e acetato) podem substituir, em parte, a glicose, quando os níveis sangüíneos desta encontram-se elevados. Quando oxidado, o lactato chega a responder por 21% do consumo cerebral de O_v Em situações de isquemia e inflamação infecciosa, o tecido cerebral passa de consumidor a produtor de lactato. Os corpos cetônicos também podem reduzir as necessidades cerebrais de glicose desde que oferecidos em quantidades suficientes ao encéfalo. Entretanto, devem ser considerados como um substrato complementar e nunca alternativo da glicose, pois comprometem a produção cerebral de succinil CoA e GTP. Quanto aos demais substratos, embora apresentem condições metabólicas, não existem demonstrações consistentes de que o cérebro produza energia a partir dos ácidos graxos sistêmicos, mesmo em situações de hipoglicemia. De maneira análoga, etanol e glicerol são considerados apenas a nível de experimentação. A utilização dos aminoácidos é dependente da sua captação, limitada tanto pela baixa concentração sangüínea, como pela seletividade da BHE. A maior captação ocorre para os de cadeia ramificada e destes, a valina. A menor captação é a de aminoácidos sintetizados no cérebro (aspartato,gluconato e alanina). Todos podem ser oxidados a CO, e H₂0. Entretanto, mesmo com o consumo de glicose reduzido a 50%, a contribuição energética dos aminoácidos não ultrapassa 10%. Para manter o suprimento adequado de glicose e oxigênio, o fluxo sangüíneo cerebral é da ordem de 800 ml/min (15% do débito cardíaco). O consumo de O, pelo cérebro é equivalente a 20% do total consumido pelo corpo. Esses mecanismos, descritos como controladores da utilização de substratos energéticos pelo cérebro, sofrem a influência da idade apenas no período perinatal, com a oxidação do lactato na fase pré-latente e dos corpos cetônicos, no início da amamentação.

Palavras- chave: cérebro, substratos energéticos, metabolismo.

SUMMARY

Altrough accounting for 2% of body weight, brain has one of the greatest metabolic rates compared with other organs and systems. The energy metabolic consum is expended mainly in the maintenance of ionic gradient, essential to neuronal activity. Brain receives energy substrates from circulation, with interference of blood brain barrier (BBB). Glucose is the main substrate and has a metabolic rate so high as 150 g/day (0,7 mM/G/min). At cellular level, metabolism of glucose seems to be controlled by phosphofructokynase. If the cellular level were high enough, manose and other products like fructose 1,6 biphosphate, pyruvate, lactate and acetate can be used in the place of glucose. Lactate, when oxyded, consums at least 21 % of the cerebral needs of 0,. In ischemia and inflammatory infections, brain tissue produces lactate instead of use it. Ketone bodies reduce cerebral needs of glucose; in view of the disturbances that occur in cerebral production of succinyl CoA and guanosine 3 phosphate (GTP), they must be considered as complementary substrate but not as an alternative one. Although they can be metabolized, there are no evidences that brain could produce energy from systemic free fatty acids, even when hypoglicemia is present. Ethanol and glycerol are considered only at experimental level. Brain uptake of aminoacids occur better for long chain aminoacids, specially valine. The aminoacids that are synthetised in the brain (aspartate,gluconate and alanine) show the lower absortion rates. All aminoacids should be oxided to CO, and H,0. Even when glucose consum is reduced to 30%, aminoacid accounts for only 10% of the energetic expenditure of the brain. To maintain cerebral glucose and oxygen supply to the brain , blood flow must be at least 800 ml/min. The regulation of supply and consumption of energy substrate by the brain is changed in few situations. Among them, are included the oxidation of lactate immediately before milk diet early in development and utilization of ketone bodies at the beginning of lactation. This review includes a brief discussion about the relevance of glucose as the main energy substrate for cerebral tissue in different ages and ischemia or hypoxia.

Key words:brain, energy substrate, metabolism.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Aceite: 15-abril-1995.

Dr. Arthur Oscar Schelp - Departamento de Neurologia e Psiquiatria, Faculdade de Medicina de Botucatu, UNESP - 18618-000 Botucatu SP - Brasil.

1. Ackermann RF, Finch DM, Babb TL, Engel JJr. Hippocampal recurrent inhibition: decreased pyramidal cell firing with increased metabolism in the pyramidal cell layer demonstrated by the 2-deoxyglucose autoradiographic technique. Soc Neurosci Abstr 1981, 7:457.
2. Arizmendi C, and Medina JM. Lactate as an oxidizable substrate for rat brain in vitro during the perinatal period. Biol Neonate 1983 , 44:36-41.
3. Cremer JE, Cunningham VJ. and Seville MP. Relatioships between extraction and metabolism of glucose, blood flow, and tissue blood volume regions of rat brain. J Cer Blood Flow Metab 1983, 3:291-302.
4. Cuezva JM., Moreno FS., Medina JM., Mayor F. Prematurity in the rat: fuels and gluconeogenic enzymes. Biol Neonate 1980, 37: 88-95.
5. Edmond J. Energy metabolism in developing brain cells. Can J Physiol Pharmacol 1992, 70:Sl 18-S129.
6. Elia M. Organ and tissue contribution to metabolic rate. In Kinney JM, Tucker HE (eds). Energy metabolism: tissue determinants and cellular corollaries, Part I, New York, Raven Press, 1992, p.61-80.
7. Engel J Jr. Kuhl. DE, Phelps ME, Rausch. R, Nuwer M. Local cerebral metabolism during partial seizures. Neurology 1983,33:400-413.
8. Engel J Jr, Kuhl DE, Phelps ME and Mazziotta JC. Interictal cerebral glucose metabolism in partial epilepsy and its relation to EEG changes. Ann Neurol 1982, 12: 507-517.
9. Felig P, Marliss EB. Cahill GF Jr. Metabolic response to human growth hormone during prolonged starvation. J Clin Invest 1971, 50:411-420.
10. Gardiner RM. The effect of feeding on cerebral blood flow and oxygen consumption in the new-born calf [Proceedings]. J Physiol (London) 1979,296:54.
11. Gibson GE, Jope R, Blass J. Decreased synthesis of acetylcholine accompanyng impaired oxidation of pyruvic acid in rat brain minces. Biochem J, 1975, 148:17-23.
12. Growdom JH, Wurtman FJ. Neurotransmitter synthesis: control by availability of dietary precursors. In Carenza L et als (eds) Clinical psychoneuroendocrinology in reprodution. London: Academic Press, 1979, p 127-138
13. Harik SI. Changes in the glucose transporter of brain capillaries. Can J Physiol Pharmacol 1992, 70: SI 13-Sl 17.
14. Hawkins RA, Bibuyck JF. Ketone bodies are selectively used by individual brain regions. Science 1979, 205:325-327.
15. Hellmann J, Vannuci RC, Nardis EE. Blood-brain permeability to lactic acid in the new-born dog: lactate as a cerebral metabolic fuel. Ped Res 1982, 16:40-44.
16. Huth PJ, Schmidt M.J, Hall PV, Fariello RG, Shug AL. The uptake of carnitine by slices of rat cerebral cortex. J Neurochem 1981, 36:715-723.
17. Kasanicki MA, Pilch PF. Regulation of glucose transporter function. Diabetes Care 1990, 13:219-227.
18. Kato M, Malamut BL, Caveness WF et al. Local cerebral glucose utilization in newborn and pubescent monkeys during focal motor seizures. Ann Neurol 1980, 7:204-212.
19. Larrabee MG.Lactate uptake and release in the presence of glucose by sympathetic ganglia of chicken embryos and by neuronal cultures prepared from these ganglia J Neurochem 1983, 40:1237-1250.
10. Lassen NA.Cerebral bood flow and oxygen consumption in man. Physiol Rev 1959, 39:183-238.
11. Lebrun-Grandié P, Baron JL, Soussaline F et al. Coupling betwen regional blood flow and oxygen utilization in the normal human brain. Arch Neurol 1983, 40:230-236.
12. Ljunggren B, Ratcheson RA., Siesjö BK.Cerebral metabolic state following complete compression ischemia. Brain Res 1979, 73:291-307.
13. Newsholme EA, Leech AR(eds). Biochemistry for the medical sciences. London: John Wiley & Sons, 1983, p336-356.
14. Oldendorf WH, Crane PD, Vraun LP. Wade LA, Diamond JM. Blood-brain barrier transport of basic amino acids is selectively inhibited at low pH. J. Neurochem 1983, 40:797-800.
15. Owen ED, Reichard GA Jr.Human forearm metabolism during progressive starvation. J Clin Invest 1971, 50:1536-1543.
16. Pardridge WM, Oldendorf WH.Transport of metabolic substrates through the blood- brain barrier. J. Neurochem 1977, 28:3-12.
27. Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980, 60:143-187.
28. Rosenthal M, Sick TJ. Glycolytic and oxidative metabolic contributions to potassium ion transport in rat cerebral cortex. Can J Physiol Pharmacol 1992 ,70:S165-S169.
29. Shambaugh GE III, Angulo MC, Koehler. RR. Fetal fuels: VII Ketone bodies inhibit synthesis of purines in fetal rat brain. Am J Physiol 1984, 247:E111-E117.
30. Sokoloff L, Reivich M, Kennedy C, et al. The [14C] deoxyglucose method for the measurement of local cerebral glucose utilization: theory.procedure and normal values in the conscious and anesthetized albino rat. J. Neurochem 1977, 28:887-916.
31. Swanson RA. Physiologic coupling of glial glycogen metabolism to neuronal activity in brain. Can J Physiol Pharmacol 1992, 70:S138- S 144.
32. Sylvia AL, Rosenthal M. Effects of age on brain oxidative metabolism in vivo. Brain Res 1979, 165:235-248.
33. Takei H, Fredericks WR, London, ED, Rapoport SI. Cerebral blood flow and oxidative metabolism in conscious fischer.-344 rats of different ages. J Neurochem 1983, 40: 801-805.
34. Wieloch T, Harris RJ, Symon L, Siesjö BK. Influence of severe hypoglicemia in brain extracellular calcium and potassium activities, energy, and phospholipid metabolism. J Neurochem 1984, 43:160-68.
35. Yarowsky PJ, Ingvar DH. Neuronal activity and energy metabolism . Fed Proc (FASEB) 1981, 40:2353-2362.
36. Yoshida S, Ikeda M, Busto R et al. Cerebral phosphoinositide, triacylglycerol, and energy metabolism in reversible ischemia: origin and fate of free fatty acids. J Neurochem 1986 ,47:744-757.
37. Yoshida S, Inoh S, Asano T et al. Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain. J Neurosurg 1980, 53:323-331.
38. Yoshida S, Harik SI, Busto R et al. Free fatty acids and energy metabolites in ischemic cerebral cortex with noradrenaline depletion. J Neurochem 1984, 42:711-717.

Datas de Publicação

Publicação nesta coleção
20 Dez 2010
Data do Fascículo
Set 1995

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. Ackermann RF, Finch DM, Babb TL, Engel JJr. Hippocampal recurrent inhibition: decreased pyramidal cell firing with increased metabolism in the pyramidal cell layer demonstrated by the 2-deoxyglucose autoradiographic technique. Soc Neurosci Abstr 1981, 7:457.

[2] 2. Arizmendi C, and Medina JM. Lactate as an oxidizable substrate for rat brain in vitro during the perinatal period. Biol Neonate 1983 , 44:36-41.

[3] 3. Cremer JE, Cunningham VJ. and Seville MP. Relatioships between extraction and metabolism of glucose, blood flow, and tissue blood volume regions of rat brain. J Cer Blood Flow Metab 1983, 3:291-302.

[4] 4. Cuezva JM., Moreno FS., Medina JM., Mayor F. Prematurity in the rat: fuels and gluconeogenic enzymes. Biol Neonate 1980, 37: 88-95.

[5] 5. Edmond J. Energy metabolism in developing brain cells. Can J Physiol Pharmacol 1992, 70:Sl 18-S129.

[6] 6. Elia M. Organ and tissue contribution to metabolic rate. In Kinney JM, Tucker HE (eds). Energy metabolism: tissue determinants and cellular corollaries, Part I, New York, Raven Press, 1992, p.61-80.

[7] 7. Engel J Jr. Kuhl. DE, Phelps ME, Rausch. R, Nuwer M. Local cerebral metabolism during partial seizures. Neurology 1983,33:400-413.

[8] 8. Engel J Jr, Kuhl DE, Phelps ME and Mazziotta JC. Interictal cerebral glucose metabolism in partial epilepsy and its relation to EEG changes. Ann Neurol 1982, 12: 507-517.

[9] 9. Felig P, Marliss EB. Cahill GF Jr. Metabolic response to human growth hormone during prolonged starvation. J Clin Invest 1971, 50:411-420.

[10] 10. Gardiner RM. The effect of feeding on cerebral blood flow and oxygen consumption in the new-born calf [Proceedings]. J Physiol (London) 1979,296:54.

[11] 11. Gibson GE, Jope R, Blass J. Decreased synthesis of acetylcholine accompanyng impaired oxidation of pyruvic acid in rat brain minces. Biochem J, 1975, 148:17-23.

[12] 12. Growdom JH, Wurtman FJ. Neurotransmitter synthesis: control by availability of dietary precursors. In Carenza L et als (eds) Clinical psychoneuroendocrinology in reprodution. London: Academic Press, 1979, p 127-138

[13] 13. Harik SI. Changes in the glucose transporter of brain capillaries. Can J Physiol Pharmacol 1992, 70: SI 13-Sl 17.

[14] 14. Hawkins RA, Bibuyck JF. Ketone bodies are selectively used by individual brain regions. Science 1979, 205:325-327.

[15] 15. Hellmann J, Vannuci RC, Nardis EE. Blood-brain permeability to lactic acid in the new-born dog: lactate as a cerebral metabolic fuel. Ped Res 1982, 16:40-44.

[16] 16. Huth PJ, Schmidt M.J, Hall PV, Fariello RG, Shug AL. The uptake of carnitine by slices of rat cerebral cortex. J Neurochem 1981, 36:715-723.

[17] 17. Kasanicki MA, Pilch PF. Regulation of glucose transporter function. Diabetes Care 1990, 13:219-227.

[18] 18. Kato M, Malamut BL, Caveness WF et al. Local cerebral glucose utilization in newborn and pubescent monkeys during focal motor seizures. Ann Neurol 1980, 7:204-212.

[19] 19. Larrabee MG.Lactate uptake and release in the presence of glucose by sympathetic ganglia of chicken embryos and by neuronal cultures prepared from these ganglia J Neurochem 1983, 40:1237-1250.

[20] 10. Lassen NA.Cerebral bood flow and oxygen consumption in man. Physiol Rev 1959, 39:183-238.

[21] 11. Lebrun-Grandié P, Baron JL, Soussaline F et al. Coupling betwen regional blood flow and oxygen utilization in the normal human brain. Arch Neurol 1983, 40:230-236.

[22] 12. Ljunggren B, Ratcheson RA., Siesjö BK.Cerebral metabolic state following complete compression ischemia. Brain Res 1979, 73:291-307.

[23] 13. Newsholme EA, Leech AR(eds). Biochemistry for the medical sciences. London: John Wiley & Sons, 1983, p336-356.

[24] 14. Oldendorf WH, Crane PD, Vraun LP. Wade LA, Diamond JM. Blood-brain barrier transport of basic amino acids is selectively inhibited at low pH. J. Neurochem 1983, 40:797-800.

[25] 15. Owen ED, Reichard GA Jr.Human forearm metabolism during progressive starvation. J Clin Invest 1971, 50:1536-1543.

[26] 16. Pardridge WM, Oldendorf WH.Transport of metabolic substrates through the blood- brain barrier. J. Neurochem 1977, 28:3-12.

[27] 27. Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980, 60:143-187.

[28] 28. Rosenthal M, Sick TJ. Glycolytic and oxidative metabolic contributions to potassium ion transport in rat cerebral cortex. Can J Physiol Pharmacol 1992 ,70:S165-S169.

[29] 29. Shambaugh GE III, Angulo MC, Koehler. RR. Fetal fuels: VII Ketone bodies inhibit synthesis of purines in fetal rat brain. Am J Physiol 1984, 247:E111-E117.

[30] 30. Sokoloff L, Reivich M, Kennedy C, et al. The [14C] deoxyglucose method for the measurement of local cerebral glucose utilization: theory.procedure and normal values in the conscious and anesthetized albino rat. J. Neurochem 1977, 28:887-916.

[31] 31. Swanson RA. Physiologic coupling of glial glycogen metabolism to neuronal activity in brain. Can J Physiol Pharmacol 1992, 70:S138- S 144.

[32] 32. Sylvia AL, Rosenthal M. Effects of age on brain oxidative metabolism in vivo. Brain Res 1979, 165:235-248.

[33] 33. Takei H, Fredericks WR, London, ED, Rapoport SI. Cerebral blood flow and oxidative metabolism in conscious fischer.-344 rats of different ages. J Neurochem 1983, 40: 801-805.

[34] 34. Wieloch T, Harris RJ, Symon L, Siesjö BK. Influence of severe hypoglicemia in brain extracellular calcium and potassium activities, energy, and phospholipid metabolism. J Neurochem 1984, 43:160-68.

[35] 35. Yarowsky PJ, Ingvar DH. Neuronal activity and energy metabolism . Fed Proc (FASEB) 1981, 40:2353-2362.

[36] 36. Yoshida S, Ikeda M, Busto R et al. Cerebral phosphoinositide, triacylglycerol, and energy metabolism in reversible ischemia: origin and fate of free fatty acids. J Neurochem 1986 ,47:744-757.

[37] 37. Yoshida S, Inoh S, Asano T et al. Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain. J Neurosurg 1980, 53:323-331.

[38] 38. Yoshida S, Harik SI, Busto R et al. Free fatty acids and energy metabolites in ischemic cerebral cortex with noradrenaline depletion. J Neurochem 1984, 42:711-717.