Brain Energy Metabolism

• All of the processes in textbooks need energy
• The text will look at the topics of energy delivery, production, and utilization by the brain

Brain Energy Metabolism Importance

• Consideration of mechanisms of brain energy metabolism is important
• Features includes energy metabolism at global, regional, and cellular levels
• Molecular mechanisms couple neuronal activity to energy consumption
• Tight coupling is the basis of brain-imaging techniques like positron emission tomography (PET) and functional magnetic resonance imaging

Energy Metabolism of the Brain as a Whole Organ

• The brain is only 2% of body weight, but energy consumption processes are 25% of total body glucose utilization
• Glucose can follow metabolic pathways, but, in the brain, it is oxidized to CO2 and water

Glycolysis (Embden-Meyerhof pathway)

• Glucose phosphorylation is regulated by hexokinase, an enzyme inhibited by glucose 6-phosphate
• Glucose must be phosphorylated to glucose 6-phosphate which allow entry into glycolysis or storage as glycogen
• Two other steps in the regulation of glycolysis are catalyzed by phosphofructokinase and pyruvate kinase
• Activity is controlled by high-energy phosphates, citrate, and acetyl-CoA
• Pyruvate, through lactate dehydrogenase, is in dynamic equilibrium with lactate
• This reaction regenerates NAD+ residues downstream of glyceraldehyde 3-phosphate
• PCr is phosphocreatine

Tricarboxylic Acid Cycle (Krebs' cycle)

• Oxidative phosphorylation is related to the Tricarboxylic Acid Cycle
• Pyruvate entry into the cycle is controlled by pyruvate dehydrogenase activity that is inhibited by ATP and NADH
• Two other regulatory steps in the cycle are controlled by isocitrate and a-ketoglutarate dehydrogenase
• Activity is controlled by the levels of high-energy phosphates

Oxygen Consumption of the Brain

• Brain accounts for 20% of oxygen consumption of the entire body
• 160 mmol per 100 g of brain weight per minute
• Corresponds to CO2 production amount
• O2/CO2 relation corresponds to a respiratory quotient of nearly 1
• Carbohydrates and glucose are substrates for oxidative metabolism
• Arterial concentration of a substrate that enters the brain through the carotid artery is compared with venous blood present in the venous blood draining the brain via jugular vein
• Arteriovenous difference: indicates the utilization of substrate. A-V difference may be negative, showing metabolic pathways resulting in the production of the substrate predominate.
• Cerebral blood flow (CBF) is known, state rate of utilization of the substrate can be determmined: CMR = CBF (A-V).
• CMR = cerebral metabolic rate of a substrate

Cerebral Blood Flow rate

• CBF is around 57 ml per 100 g of brain weight per minute in normal adults
• Glucose utilization by the brain is 31 mmol per 100 g
• 6 mmol of oxygen is needed to oxidize 1 mmol of the six-carbon molecule of glucose
• Oxygen consumption rate of 160 mmol per 100 g, predicted
• Glucose utilization would be 26 mmol per 100 g: Actual measured is 31 mmol
• Excess 4.4 mmol can proceed to a limited extent through glycolysis, making lactate without oxygen consumption
• Can be included into glycogen
• Glucose is a factor of macromolecules like glycolipids and glycoproteins present in neural cells
• Can result in the synthesis of three neurotransmitters of the brain: glutamate, GABA, and acetylcholine

Ketone Bodies Energy Substrates for the Brain: Special Circumstances

• Substrates other than glucose utilized: ketone bodies acetoacetate (AcAc) and D-3-hydroxybutyrate (3-HB)
• Interesting example of developmentally regulated adaptive mechanism due to maternal milk high in lipids
• Leads to increased lipid to carbohydrate ratio than that in postweaning nutrients
• 55% of calories from human milk, 30-35% of calories from balanced postweaning diet
• Other lipid metabolism products relevant include free fatty acids
• AcAc, 3-HB, and free fatty acids can be processed to acetyl-CoA to provide ATP through the TCA cycle
• Brain energy metabolism is highly compartmentalized, and specific pathways localized

Ketone Bodies and Brain Cell Types

• Ketone bodies can be oxidized by neurons, oligodendrocytes, and astrocytes
• Β-oxidation of free fatty acids is localized in astrocytes
• Period's contribution regards lipid-rich diet provided during suckling and its relation to myelination process
• Lipids and cholesterol derived from dietary sources synthesis in the brain
• Lipids synthed from blood-borne precursors such as ketone bodies
• Suckling rats on diet low in ketones means carbon atoms for lipogenesis provided by glucose
• Ketone bodies and AcAc are energy substrates and precursors for lipogenesis during the suckling
• Developing brain may be flexible because glucose can be metabolized to synthesize substrates for lipid synthesis

Lack of Glucose Availability

• Occurs both in starvation and diabetes is inadequate. The plasma ketone bodies are elevated as lipid catabolism increases under this condition.
• Breast-fed neonates adaptive mechanisms
• AcAc or 3-HB can be utilized as energy substrates
• Number of metabolic intermediates are tested as an alternative substrate to glucose for brain energy metabolism
• Mannose sustains normal brain function, crosses the blood-brain barrier readily and is converted into fructose 6-phosphate
• Not present in the blood and not a physiological substrate for brain energy metabolism

Lactate and Pyruvate Properties in Brain Tissue

• Isolated brain tissue
• Brain as an organ receiving substrates from the circulation
• Can sustain the synaptic activity of isolated brain samples
• Maintained in vitro in a physiological medium lacking glucose
• Permeability across the blood-brain barrier limited
• Prevents circulating lactate or pyruvate to substitute for glucose
• Maintain brain function
• Permeability of circulating lactate across the blood-brain barrier may be high
• Presence of monocarboxylate transporters on intraparenchymal brain capillaries documented
• Needs reappraisal of the use by the brain of monocarboxylates
• Formed within the brain parenchyma from glucose that crossed the blood-brain barrier

Energy Substrates for Activated Neurons

• Lactate and pyruvate act as the preferential energy substrates
• Obligatory energy substrate for brain, almost entirely oxidized to CO2 and H2O
• Ketogenic conditions results in ketone bodies as possible energy
• Formed from glucose within parenchyma, and adequate energy substrates as well

Coupling of Neuronal Activity, Blood Flow, and Energy Metabolism

• The brain has a structural, and functional specialization
• When we move an arm, related pathways are activated selectively
• As "brain work" increases locally, energy requirements of the activated regions will increase in a temporally and spatially coordinated manner
• Energy substrates come through circulation in blood
• Blood flow increases in the modality-specific activated area
• The brain has intrinsic mechanisms by which vascular supply can be varied locally in correspondence with local variations of functional activity
• Chemical products of cerebral metabolism produced in the course of neuronal activation supply activity with increased blood flow

Chemical Mediators and Neuronal Activity

• Signals are classified as molecules that accumulate in extracellular space following neuronal functions and specific neurotransmitters that conduct the coupling in anticipation/parallel with local activations (neurogenic mechanisms)
• These signals are temporary changes in extracellular K+ and the molecules and ions from ATP with respect to pH

Molecules and Neurogenic Mechanisms

• Have roles as coupling mediators because of vasoactive effects
• Spatial/temporal resolution might not explain resolution-coupling between activity/blood because of the delay in their effects
• Brain microvessels innervated by neuronal fibers and of extrinsic/intrinsic origins
• Functional transmitters have recognized coupling transduction pathways on intraparenchymal microvessels
• Neurotransmitters for activity/blood coupling potential: amines and peptides
• Mode coupling describes neurotransmitters released vasc fibers activating discrete volume Nitric oxide also joins the listed coupling mediators because of its formation from neurons/glial through the actions of neurotransmitters through depolarized afferants in a brain
• It is a possible dilator whose half-life controls its field of activation
• In inhibiting nitric oxide synthase, residual synergy acts as a reminder of the network regulation in the local flow of blood

Summary of Neurotransmission

• Products of activity-dependent neuronal/glial metabolism such as lactate, H, adenosine, K have vasoactive effects
• Kinetics do not cover phenomena
• Pure neurogenic activity flow modes uncommon. Nitric oxide is a coupling portion
• Glutamate may produce a link from activity
• Substrates glucose and oxygen are given to the area to fulfil demands unit/time

Visualization and Measurement in Humans

• Imaging techniques let monitor function in humans
• PET indicates the rate
• Glucose and oxygen monitored non-invasively in subject