Energy Metabolism in the Brain

Question 1

Why does the brain need energy? (4)

Answer 1

• Energy heavy organ - using 20% oxygen and 25% of circulating glucose
• 15% of body’s total blood flow
• Supply and demand of energy requires dynamic adjustments in cerebral blood flow and glucose
  consumption
• Brain metabolism is highly compartmentalized and
  numerous biochemical processes are involved
• analogy: running a marathon all day, everyday

Question 2

Different energy requirements of the brain (5)

Answer 2

• Glucose is the primary source of energy used by both neurons and astrocytes
• Lactate, a special role as a readily available source of energy
• Ketone bodies eg acetoacetate and β-hydroxybutyrate = essential substrates
• Age and development influences energy demand
• Distribution of energy amongst cell types vary

Question 3

describe the change in substrate preference in line with development (2)

Answer 3

early brain dev: lactate + ketone - immediate postnatally => coincides w/ high fat content in milk of humans + animals

shift due to availability of substrate + changes in transport proteins = glucose

Question 4

when else is lactate or ketone used as a substrate other than as a baby? (2)

Answer 4

When glucose isn’t available - ie extreme energy consumption (neuroinflammation)

ketone diets

Question 5

How do we measure brain energy? (7)

Answer 5

• ATP production (primary energy currency - brain’s energy status, response to stim - norm vs abnorm)
• Rate at which glucose is consumed (brain’s utilisation of glucose)
• Rate of oxygen consumption (energy production)
• Lactate production and uptake (brain;s reliance to lactate)
• Cerebral blood flow (ensures delivery of O2 + gluc to meet energy demands)
• Mitochondrial function (measuring ATP synth, o2 consump. etc)
• Energy metabolism rate (holistic view of brain’s energy metab.)

Question 6

what does recent evidence show about cell’s energy usage? (3)

Answer 6

major distribution of energy = uncertain how much

oligodendrocytes use less energy/metabolic rates than neutrophil regions eg astrocytes/ neurons

neuronal cell bodies glucose utilisation < astrocytes/ regions rich in synapses

Question 7

Energy Metabolism def (1)

Answer 7

The set of chemical reactions and processes for acquiring, storing, and utilizing energy from nutrients (carbohydrates, fats, proteins)

Question 8

Energy Metabolism background (4)

Answer 8

core process: catabolism of nutrients -> ATP

key processes: Glycolysis, TCA cycle (KREBS/citric acid cycle), oxidative phosphorylation, lipolysis etc

location: all cells esp liver, muscles, adipose

importance: Fundamental biological process, responsible for energy production

Question 9

Energy homeostasis def (1)

Answer 9

The body’s capacity to maintain a stable
balance between caloric intake and
expenditure to maintain overall energy
equilibrium

Question 10

Energy homeostasis background (4)

Answer 10

core process : Regulatory mechanisms controlling hunger, appetite, satiety + energy expenditure to avoid energy excess/deficiency

key processes: Neural and endocrine control mechanisms, especially involving the hypo

location: organism level - reg entire body energy balance

importance: Essential for maintaining healthy body weight and preventing obesity or excessive weight loss

Question 11

Describe the makeup of the BBB (4)

Answer 11

metabolic barrier/ neurovascular unit

innermost = Brain capillary lumen
next layer = endothelial cells
3rd layer : basement membrane with pericytes in it
4th layer: astrocytes

Question 12

What is a pericyte? (2)

Answer 12

specialised cell residing in the walls of capillaries + integral component of neurovasculature - maintains BBB integrity

Question 13

What is the astrocyte’s role in the BBB? (2)

Answer 13

central role in the uptake of glucose from bloodstream to projections

= serves as a protective barrier b/w blood supply + neuron

Question 14

Describe the pathway of glucose in the BBB (7)

Answer 14

glucose uptake via GLUT1 from brain interstitial fluid to endo cell
- conversion into pyruvate
- conversion into lactate

transport via MCT1/5 into BM
transport via MCT12 into pericyte
- lactate -> pyruvate conversion
- TCA cycle = ATP

Question 15

CVO background (5)

Answer 15

organs w/o BBB + instead highly permeable capillaries (highly vascularised)

lining 3rd + 4th v of brain

act as windows of the brain

either sensory or secretory (or both)

serve as homeostatic monitoring centres = closely observing any systematic circulatory changes -> releasing neuropeptides into circulation

Question 16

Explain the difference b/w secretory + sensory CVO’s (2)

Answer 16

sec: some release directly into bloodstream or CSF

sen: equipped to monitor the peripheral circulation + adapt accordingly to nay detected changes

Question 17

Name the 2 main glucose transporter in brain metabolism + the differences b/w astrocytes + neurons (2 + 2)

Answer 17

• SLC2 family – Glucose transporters (Glut) - Na+ independent
• SLC16 family – MCT transporters - crucial role in facilitating glu + monocar acids into brain

A: (SLC2A1) GLUT1 + MCT 1/4
N : (SLC2A3) GLUT3 + MCT 2

Question 17

why does glucose need transporters? (1)

Answer 17

because it’s hydrophilic

Question 18

Discuss the change in transporter proteins in line w/ development in the Astrocytes + neurons (2)

Answer 18

During brain development:
there is high numbers of MGLUT1 but even higher numbers of MCT1 in the brain: due to lactate + ketone substrate preference + availability

during brain maturation + synaptogenesis:
switch to increase exponentially the number of MGLUT1 transporters and decrease in the number of MCT1 transporters due to the change in fuel pref to glucose

Question 19

Is there a diff in the amount of glucose uptake in neurons + astrocytes? (1)

Answer 19

no - despite diff transport proteins, they take up approx equal proportions

Question 20

How does the brain sense blood
glucose? (2)

Answer 20

Glucose sensing is achieved in 2 ways:
o Sensing blood glucose in tight capillaries via tanycytes - send projections into nuclei

o CVOs with leaky capillaries via neurons and tanycytes

Question 21

where are tanycytes found? (1)

Answer 21

lie at interface b/w ventricles + ventricular CSF - mostly on floor of 3rd v

Question 22

Name the anabolic pathways (1)

Answer 22

Biosynthesis: Several enzymatic pathways lead to the synthesis of biological molecules eg more enzymes or structures like hair

Question 23

Name the catabolic pathways (2)

Answer 23

eg Glycolysis + Cellular respiration: Several enzymatic pathways break down small molecules eg sugars into even smaller molecules to release ATP

digestion: Several enzymatic reactions occur in our digestive tract to breakdown food into smaller molecules that can easily be absorbed into the
blood stream and into our cells

Question 24

State the approx total energy use of teh brain (3)

Answer 24

• 21µmol ATP/g/min
  – approx 75% = signalling
  – approx 25% = maintaining non-signalling activity eg protein syn + degrad, nucleotide and phospholipid turnover, axoplasmic transport and mitochondrial proton leak

Question 25

Why glucose? (4)

Answer 25

• Dynamic energy source = glycogen (glycolysis)
• glycolysis = Energy production & biosynthesis of:
  Carbohydrates
  Amino sugars
  Neuromodulators
  Amino acids

-pentose phosphate shunt pathway = NADPH formation + Nucleotide biosynthesis

• TCA cycle = Amino acids + neurotransmitters

Question 26

Describe the steps of glycolysis (5)

Answer 26

1) glucose - 1ATP
—hexokinase—

2) glucose -6- phosphate
3) fructose -6- phosphate - 1 ATP
— phosphofructokinase 1—

4) Fructose-1,6 - bisphosphate

either anaerobic (+) or aerobic resp
- ana:
then aerobic
then TCA cycle/ kreb cycle

• aer:
  malate- aspartate shuttle
  then electron transport chain
  then oxidative phosphorylation

Question 27

What happens with glucose in the
brain - neurons vs astrocyte glucose metab (2)

Answer 27

• Neurons rely on oxidative metabolism ( or via lactate given by astrocytes via bloodstream)
• Astrocytes predominantly metabolizing glucose via glycolysis