Cellular Mechanisms of Brain Energy Metabolism
- To present an overview of energy metabolism in the brain in humans
- How we know that glucose is the major fuel in the brain
- THE CNS REQUIRES A CONTINUOUS SUPPLY OF BLOOD TO MAINTAIN ITS HIGH METABOLIC ACTIVITY
- Major fuel for the brain
- Most cells in the brain cannot utilize fatty acids
- Brain cells to not store much glycogen hence their dependence upon blood glucose!
- Brain cells have low Km glucose transporters
- So tight glucose binding
- GLUT1 and GLUT3: this way have “first crack” at the available glucose levels
Glucose metabolism in neurons
- Glucose is completely oxidized in order to generate large quantities of ATP
- Glycolysis in which hexokinase (lowKm) catalyzes the first step, is followed by PDC activity with the resulting acetyl-CoA entering the TCA cycle
- PDC: involves 5 coenzymes derived from 5B vitamins – in Beri Beri due to thiamine deficiency, get neurological symptoms
Ketone bodies as fuel for brain:
- Can also be utilized as fuels in the brain, BUT blood levels in the brain are normally insufficient to compete with flucose
- Marked ketonemia: occurs in long-term starvation (BUT not just fasting!) and allows the subject to reduce gluconeogenesis (from protein) and therefore survive!
Glucose as fuel in the brain
The obligatory energy substrate for brain and it is almost entirely oxidized to CO2 and H2O
An extended period of profound hypoglucemia
- <18mg/dL can induce massive cerebral energy failure and neuronal necrosis: !
- Levels of 50-65mg/dL can lead to short-term cognitive impairment (relate to car driving/accidents in diabetes)
A cell-specific sequence of processes
Eventually leads to the almost complete oxidation by the brain of blood-borne glucose
More on glucose as the major fuel for brain
- Is about 2% ob body weight
- Receives 15% of the CO
- Responsible for 2-% of total body O2 consumption!
- Responsible for 25% of total body glucose utilization
- Extracts approximately 50% of oxygen from the arterial blood
- Extracts 10% of glucose from the arterial blood
- NOTE: O2 consumption and CO2 production in brain are almost identical! – RQ=1
The Astrocyte-Neuron Connection and Glucose Metabolism
- The maximum rate of glucose uptake: 700nmoles/g/min
- The maximum rate of lactate uptake in neurons is: 60 nmole/g/min
- Palmitate (saturated C16FA) has an uptake rate of <0.01 nmoles/g/min:
- Lactate and Pyruvate: because of their limited permeability across the BBB, CANNOT substitute for plasma glucose to maintain brain function
- However, Lactate and Pyruvate: are formed inside the brain parenchyma, they are useful metabolic substrates for neural cells
- The brain does, however, take up som essential FAs from the blood.
Neurons express which glucose transporters?
Astrocyte end-feet cover virtually all endothelial capillary walls and have which glucose transporter?
Glutamate-Induced Glycolysis in Astrocytes During Physiological Activation
- When neurons use Glutamate as neurotransmitter, they can’t re-uptake it directly
- Astrocytes uptake glutamate through co-transport with 3Na ions
- Astrocytes then convert glutamate to glutamine which can be transported into a neuron and be used again to synthesize glutamate in mitochondria within the neuron
- Increased intra-astrocytic Na+ leads to activation of the sodium-potassium pump to bring the equilibrium back to the cell AND also stimulates glycolysis whereby LACTATE IS PRODUCED
Astrocytes get glucose from capillaries
- Then do glycolysis with it and eventually produce 2 lactates from 1 glucose
- The lactate then leaves the astrocytes and neurons are free to pick it up and use it as fuel
The Proposed Astrocyte-Neuron Lactate Shuttle
- Pyruvate metabolism via PDC and the TCA cycle leads to the net production of 17 ATPs per lactate
- Exchange of lactate between astrocytes and neurons is operated by monocarboxylate transporters (MCTs)
Brain metabolism in the neuron:
- Glucose to G-6-P to F-6-P to F-1,6-BP to pyruvate to acetyl-CoA into the TCA Cycle
- PFK-1 controlled – activated by: AMP & F-2,6-BP
Brain metabolism in the astrocyte
- Glucose to G-6-P to F-6-P to F-1,6-BP to pyruvate to lactate
- PFK-1 activity increased by [ATP]
Complete oxidation of 2 lactates produces about__________ATP
2 lactates equivalent to about 1 glucose, so about 34 ATPs
How does lactate get transported between cells?
- MCTs are electroneutral and mediate the H+-coupled flux of lactate, pyruvate or other monocarboxylates across cell membranes of most tissues in the body. In the case of lactate, MCTs can operate in either the net inward or net outward direction, depending on the lactate and H+ gradients across the cell membrane. MCTs probably moves lactate OUT of cells that produce lactate by glycolysis and INTO cells that consume lactate.
- MCT1 and MCT4 in astrocytes ensure lactate release MCT2 in neurons allows for uptake of the lactate.
Role of glycogenolysis in Astrocytes
- In the Figure, reactions occurring in astrocytes but not in neurons are indicated by heavy arrows.
- Glycogen breakdown in astrocytes occurs in response to transmitters
- Brain turnover of glycogen is increased during activation
- Alpha-KetoGlutarate is the precursor of Glutamine which ends up being the source of Glu for neurons (via Glutamine).
- In young chickens, inhibition of glycogenolysis interrupts memory consolidation: !
What is cotransported with glutamate from the synaptic cleft?
The subsequent decrease in ATP in astrocytes activates which enzyme in which pathway?
The metabolism of lactate in neurons has which end products?
- And lots of ATP: 17
The metabolism of lactate in neurons generates how much ATP?
Which enzyme’s activity would limit glycolysis in neurons and what controls that enzyme?