Brain Energy Metabolism

NeuroMet

In energetic terms, the mammalian brain is an expensive organ. While comprising only two percent of the body mass of an adult human, it utilizes twenty percent of the total (resting) energy consumption (McKenna et al. 2006). Thus, the metabolic cost of brain activity is high and this might indeed be the limiting factor for both the number of neurons that can be active at any given time, as well as the maximum frequency of firing of individual neurons, as argued by Lennie (2003) and Attwell and Gibb (2005), respectively. Over the years, several attempts have been made to provide an energy budget for signaling in the mammalian brain/grey matter (Astrup 1982;Attwell and Laughlin 2001;Creutzfeldt 1975).

Basically, what is causing this huge consumption of energy is the restoration of the membrane gradient following neuronal depolarization which is accomplished by the Na⁺/K⁺-ATPase. The human brain contains the largest density of Na⁺/K⁺-ATPase molecules in the body (~11.000 pmol/g tissue), the heart taking second place by a number more than 20 times lower (~500 pmol/g tissue (Clausen 1998). Under normal physiological conditions, the primary fuel for the brain is glucose (McKenna et al. 2006); however, lactate taken up from the blood might play a role during exercise (Dalsgaard 2006). And indeed, as has been known for more than 5 decades (McIlwain 1953) nerve tissue activity may be fuelled by other substrates than glucose, including lactate. In theory, this applies to all substrates that can be oxidized in the tricarboxylic acid (TCA) cycle, including all α-amino acids (the glucogenic amino acids via a process known as pyruvate recycling).

Most if not all of the brain glycogen is localized in astrocytes (Cataldo and Broadwell 1986). Glycogen constitutes the main energy reserve of the brain; however, the glycogen store may only sustain brain metabolic turn-over for a few minutes at most (McKenna et al. 2006). Thus a role for glycogen only during hypoglycemia is unlikely. The real debate is whether glycogen is a dynamic source of glucose units during normal function of the brain, which would seem highly likely given the fact that in the thin astrocytic processes sheathing the synapses, there is no room for mitochondria; however, glycogen granules are widespread making it likely that anaerobic glycolysis may be important in this subcellular compartment (review, Hertz et al. 2006).

Although the longstanding dogma of the brain as an organ relying solely on glucose for energy production is still largely valid to this day, a debate on whether neuronal oxidative metabolism rely on astrocyte-derived lactate over glucose during neurotransmission activity has been initiated (Pellerin and Magistretti 1994). This hypothesis is, however, highly controversial (e.g. Hertz, 2006). The role of different energy substrates for neural metabolism is the object of current research in the Neurometabolism Research Unit. 

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