Lecture 33: Coordinating metabolism - fuel mobilisation

Question 1

What is the importance of fuel mobilisation in the body?

Answer 1

An important part of metabolic homeostasis is the body’s ability to rapidly convert stored macronutrients into usable energy.

This is required to meet its energy demands during periods of fasting, stress and activity.

Question 2

What is the name for the fuel mobilisation processes in the body for carbohydrates, fats and proteins and what are these processes controlled by?

Answer 2

• For carbohydrates, the process of glycogenolysis is activated to obtain glucose for glycolysis.
• For fats, lipolysis is activated to obtain FAs for B-oxidation.
• For proteins, proteolysis to obtain amino acids for energy

These processes are controlled by the hormones, glucagon and adrenaline with some tissue specificity.

Question 3

Where is glucagon synthesised and what is its release stimulated by?

Answer 3

Glucagon is produced in pancreatic a-cells

Secretion is stimulated by:
* Fasting and starvation
* Low blood glucose
* Amino acids
* Exercise (particularly prolonged or intense)
* Stress via adrenaline

Question 4

What is adrenaline, where is it synthesised and what is its role?

Answer 4

• Adrenaline (epinephrine) is a hormone and neurotransmitter.
• Synthesised from tyrosine in adrenal glands (medulla).
• Primes the body for a “fight or flight response” i.e. increased heart rate, bronchodilation, redirects blood flow to muscles and increases blood sugar.

Question 5

What is the main role of glucagon?

Answer 5

Glucagon has the opposite action to insulin
i.e. it raises blood sugar

Question 6

What stimulates the release of adrenaline?

Answer 6

• Released on physical or psychological stress perceived by the hypothalamus and signaled to adrenals via the sympathetic nervous system.
• Release also triggered by low blood sugar and intense exercise.

Question 7

What are the similarities of Glucagon receptors on liver and adrenaline receptors on muscle?

Answer 7

• Both hormones bind G protein coupled receptors (GPCR).
• Binding induces a conformational change that activates the G-protein.
• Activated G protein subunit activates adenylyl cyclase enzyme.
• Increases in cAMP levels (secondary messenger).
• cAMP activates PKA via allosteric activation.
• PKA activity can activate or inhibit downstream enzymes.

Question 8

What are the hormones responsible for mobilising glycogen in the liver and muscles respectively?

Answer 8

Glycogen mobilisation (glycogenolysis): Initiated by

• Glucagon in liver
• Adrenaline in liver and muscle

Question 9

What is the mechanism used to trap glucose in the cell once it enters?

Answer 9

Once inside the muscle cell, glucose is quickly phosphorylated by an enzyme called hexokinase, turning it into glucose-6-phosphate (G6P).

This prevents glucose from leaving the cell and traps it inside for further processing.

Question 10

How is GPCR signaling pathway downregulated (eg. how is it reset to be ready to receive another signal)?

Answer 10

Ligands diffuse away from receptor.

Intrinsic GTPase activity in the activated Gs subunit of the G protein converts it back to the inactive (GDP-bound) state.

cAMP secondary messenger is metabolized by phosphodiester enzyme (PDE).

PDE is inhibited by caffeine hence its stimulatory action.

Phosphatases remove phosphate groups on phosphorylated proteins

The signal has now been reset ready for another stimulus

Question 11

Lipopolysis in adipose is also activated via glucagon
(and adrenaline) signaling… How?

Answer 11

In this case the activated PKA phosphorylates and activates hormone sensitive lipase which hydrolyses the TAGS in fat droplets.

The released FFAs are bound to albumin and transported to tissues.

The released glycerol can be used to make new glucose in liver

Question 12

Hormone sensitive lipase breakdown adipose tissue releasing glycerol and FFA’s. What are the fates of this mobilised fuel?

Answer 12

Glycerol:
Enters blood and goes to liver where it can be used
to synthesise glucose

Free Fatty Acids (FFA) (complexed to albumin in blood):
- Used by all aerobic tissues
- EXCEPT brain

Question 13

How does glucagon stimulate B-oxidation?

Answer 13

1. Upregulates the transcription of genes required for B-oxidation i.e. carnitine acyltransferases
2. Downregulates DNL i.e. the synthesis of new fatty acids

Question 14

Can protein be mobilised as fuel in the body?

Answer 14

Yes but avoided if possible:

• 10 - 15 kg protein in body.
• BUT no specific storage proteins.
• Some protein must be degraded to amino acids to make
  glucose (see lecture 28)
• Loss of too much protein causes structural and
  functional damage.
• Protein must be conserved as much as possible

Question 15

Describe the fueling of aerobic and anaerobic exercise in muscle:

Answer 15

Aerobic exercise (requires O2 , low intensity, prolonged)
* Glucose from blood (or from glycogen as glucose-6-P)
undergoes oxidative metabolism as does fatty acids

Anaerobic exercise (doesn’t requires O2 , high intensity for
short periods)
* Glycogen to glucose-6-P and anaerobic glycolysis
* Phosphocreatine

Question 16

Describe with more detail the generation of ATP for aerobic muscle use:

Answer 16

• Blood supplies fuels
• Blood supplies O2
• Active citric acid cycle
• Electron transport chain - oxidative phosphorylation

Question 17

Describe anaerobic glycolysis: How is ATP generated?

Answer 17

• Muscle glycogen source of fuel.
• O2 not required.
• ATP generated by substrate-level-phosphorylation.
• Pyruvate reduced to lactate to regenerate NAD+.
• ATP generation very rapid but for short time only.
• Lactate can cause muscle pH to drop, thus fatigue.

Question 18

Describe the role of phosphocreatine in anaerobic exercise: What amino acids is it made from (3)?

Answer 18

• Is “on site”, “fast fuel”, provides energy buffer.
• Made from Gly, Arg and Met.
• Is a ‘high-energy phosphate’ compound.
• Phosphate can be transferred to ADP to make ATP.
• 20 µmol per g muscle provides ~10 s worth of ATP