Energy metabolism in developing brain cells

Abstract

During development different energy substrates are available to cells in brain in plentiful supply. The metabolic environment, which is dictated by the milk diet rich in fat, ensures that substrates in addition to glucose are available as fuels. Some substrates serve readily as primary fuels for respiration, whereas other substrates can serve other functions in addition to serving as primary fuels. Primary fuels for respiration serve to supply acetyl CoA directly and as a result always have first priority. With this criteria in mind, a consideration of substrate priority for respiration by developing brain is presented. Many studies in the decade, 1970–1980, in human infants and in the rat pup model show that both glucose and the ketone bodies, acetoacetate and D-(−)-3-hydroxybutyrate, are taken up by brain and used for energy production and as carbon sources for lipogenesis. Products of fat metabolism, free fatty acids, ketone bodies, and glycerol dominate metabolic pools in early development as a consequence of the milk diet. This recognition of a distinctive metabolic environment from the well-fed adult was taken into consideration within the last decade when methods became available to obtain and study each of the major cell populations, neurons, astrocytes, and oligodendrocytes in near homogeneous state in primary culture. Studies on these cells made it possible to examine the distinctive metabolic properties and capabilities of each cell population to oxidize the metabolites that are available in development. Studies by many investigators on these cell populations show that all three can use glucose and the ketone bodies in respiration and for lipogenesis. Only one cell type, the astrocytes, can β-oxidize fatty acids such as octanoate. By comparing the production of labeled carbon dioxide from glucose labeled on carbon-1 compared with carbon-6, it is clear that all three cell populations are capable of active hexose monophosphate shunt activity. Neurons and oligodendrocytes are capable of making good use of acetoacetate and D-(−)-3-hydroxybutyrate, whereas the best substrate for astrocytes is fatty acid. Under comparable conditions of incubation with astrocytes, fatty acids serve better than ketones, which in turn serve better than glucose in respiration. Some of the major factors that can explain the differing observations by different investigators on the capacity for substrate oxidation are presented. Over the last decade, astrocytes have captured the attention of neurobiologists because they have special attributes as metabolic support cells for the management of intermediary metabolism in brain. Evidence has been accumulating that astrocytes exhibit a versatility in their metabolic competency and are now regarded as metabolically multifunctional. Unlike neurons or oligodendrocytes, the astrocytes in culture exhibit metabolic versatility and substrate specialization in their management of carbohydrate and in the processing of fatty acids by β-oxidation, which also produces acetoacetate. In this regard astrocytes process substances important for other cells. Blood-borne ketone bodies are not mandatory substrates for growth and brain development of the infant rat. In addition, it is known that the developing brain is autonomous with respect to meeting its needs for major lipids such as cholesterol and palmitate, consequently a reliable substrate supply to support and fuel these needs is mandatory. Evidence is now available to support the conclusion that the developing brain can accommodate alternative substrates to meet its needs for respiration and cholesterogenesis. A metabolic adaptability is demonstrated in vivo when it is shown that increased glucose utilization compensates for the reduced availability of acetoacetate in a dietary induced hypoketonemic state in neonatal rat pups that are fed milk substitutes. This compensation is implemented without the precocious development of the key neural enzyme, pyruvate dehydrogenase, which would be expected to facilitate an increased flux of glucose-derived pyruvate for respiration and lipogenesis.Key words: developing brain, neural cells in primary culture, primary fuels, respiration, fatty acids, ketone bodies, glucose.