S2: Integration of Whole Body Metabolism

Question 1

How do organs and tissues use the same molecule in different ways?

Answer 1

e.g. on using it to store, other for energy source, or to generate a new molecule – biosynthesis

Question 2

Describe how glucose gets into the brain

What happens is plasma glucose drops too low?

Answer 2

The brain lacks energy stores however, so in order for it to use glucose it has glucose transporters appropriate for its needs. This is GLUT3, which has a low Km, meaning it’s maximally active at concentrations of glucose that would be seen at any time, so even when below normal – it is saturated under most conditions. This is good because it won’t be affected by fluctuations in glucose, so brain won’t be starved of its main energy source.

Danger point is when plasma glucose drops below 2.2mM.
Normally fatty acids are used not for energy but for membrane synthesis (but will use them if in dire need, as well as ketone bodies).

Question 3

Why does the brain require a lot of glucose?

Answer 3

50% of the energy consumed is used for Na+/K+ transport to maintain the membrane potentials of neurones and also for synthesis of neurotransmitters.

Question 4

Describe energy consumption of cardiac muscle

Answer 4

Cardiac muscle is dependent on aerobic respiration (if you deprive = angina).
It has little/no glycogen stores, instead its main source of energy is fatty acids, supplied by the liver. Followed by ketone bodies and lactate.
The reason why fatty acids is because it yields a much greater amount of ATP when compared to glucose.

Lactate –>Pyruvate –> acetyl CoA

Question 5

Describe energy storage of adipose tissue

Answer 5

Adipose tissue is the main reservoir of metabolic energy in the form of triglycerides, being stored. Most of these fats have been made by the liver and then transported to the adipocytes, although adipocytes can synthesise fat themselves.

Overall, the majority of FA we get from our diet, that have been delivered by chylomicrons or as intermediate through the liver.

Question 6

What is the main energy source of the kidney?

Answer 6

Glutamine

Question 7

What organ contributes half of the blood glucose through gluconeogenesis during starvation?

Answer 7

Kidney

Question 8

The liver plays a central role in regulating metabolism for…

Answer 8

• Carbohydrates
• Fatty acids
• Amino acids

Question 9

What is the main energy source of the liver?

Answer 9

The liver itself takes its energy from α-ketoacids (α-ketogluterate, pyruvate, oxaloacetate)

Question 10

What enzyme does the liver have that other tissues font have?

Answer 10

The liver has a different enzyme make up compared to other tissues, quite importantly it has glucokinase enzyme as well as hexokinase for phosphorylating glucose.
Glucokinase has a high Km, so only maximally active when glucose conc. is elevated, it is there to help keep blood glucose constant.

Question 11

Describe Control of Blood Glucose by Liver Metabolism

Answer 11

Glucose is transported into hepatocytes by GLUT-2, which activity is not regulated by insulin. Glucose is immediately phosphorylated to G6P by glucokinase.

Glucose-6-phosphatase is present in the liver (from glycogen breakdown) also allowing conversion of G6P to glucose in gluconeogenesis/glycogenolysis which can be transported out of cell into blood by GLUT-2

Question 12

Describe Muscle Glucose Metabolism

Answer 12

Muscle has a different glucose transporter, the GLUT-4 (insulin dependent). It is converted into G6P once inside by hexokinase (low Km, so equilibrium towards G6P) -> allowing low glucose conc. in the cell. Muscle doesn’t have glucose-6-phosphatase so cannot convert G6P back to glucose. Instead the G6P will be used for synthesis of glycogen or immediate use in glycolysis when G6P is a rapid source of ATP.

So muscle uses energy through oxidation of glucose but also stores it, but only for its own use.

Question 13

How is fuel used for a sprint or marathon?

Answer 13

ATP in both cases directly powers myosin for contraction of muscle (chemical energy to movement). Resting muscle uses fatty acids as a major source of energy.

Power and speed is dependent on rate of ATP production.

Question 14

What powers a sprint?

Answer 14

ATP stores - used quick
Glycolysis - anaerobic (lactate produced)
Glycogen -> for short time it is mobilised
Creatine phosphate

Anaerobic breakdown of glycogen stores gives lactate and a fall in pH

Question 15

How is creatinine phosphate used as an energy source?

Answer 15

Muscle contains creatine phosphate which can react with ADP to give ATP and creatine (it is a small store of ATP)

Creatinine phosphate +ADP ATP +creatinine

This uses the enzyme creatine kinase

Question 16

Difference between fuel for sprint and marothon

Answer 16

Sprint is an anaerobic activity but impossible for marathon which has to be aerobic

Sprinter = uses glucose
Marathon runner = use fatty acids -> generate Acetyl CoA -> TCA, some protein may also be broken down (as need to maintain blood glucose so brain has enough)
Even in a marathon there will be some generation of lactate

Question 17

Describe fuel for a marathon

Answer 17

Amount of ATP required (needs to be generated over a longer period of time) exceeds that stored by the muscle so coordination between muscle, liver and adipose tissue is needed.
- Aerobic respiration is used

Fats are a large source of ATP, the metabolism is slower than glycogen and 10x slower than creatine phosphate. It is therfore more efficient to use both fat and glycogen and this is regulated by synthesis of acetyl CoA from fat which regulates glucose into TCA.

Question 18

How is alanine and lactate formed and what are they used for?

Answer 18

We get our alanine through protein degradation and lactate through anaerobic respiration. These can be transported in the circulation to the liver where they are fed into gluconeogenic pathway.
This glucose can be used as an energy source for muscle or put into circulation to maintain circulating levels for the activity of the brain.

Question 19

What is the cori cycle?

Answer 19

Lactate back to glucose

Question 20

Describe what happens to metabolism (energy usage) in the fed state

Answer 20

In the fed state blood glucose will be maintained and brain will take what is needed. If there is excess calorific intake (through carb), then that excess will be converted to fatty acids and stored in adipocytes. It may also be transported to muscle where a little can be stored as fat or glucose as glycogen.

With regards to pathways—
- Glycolysis increase
- Glycogen synthesis increase
- Glycogenolysis + Gluconeogenesis decrease (-> don’t want to produce glucose when sufficient levels in blood)
- Fatty acid synthesis increase
- Fatty acid degradation decrease

With regards to molecules:
- Glycogen increase
- Glucose decrease
- Fatty acid increase	- Ketone bodies decrease

Question 21

Describe metabolism(energy usage)in post-absorptive phase

Answer 21

Post-absorptive phase is several hours after the last meal or if you restrict your diet. The main energy source to re-stablish glucose levels is glycogen. Hence there will be an increase in phosphorylase a activity to increase glycogen breakdown (glucose conc. in portal blood will fall leading to increase in active form of enzyme phosphorylase a in the liver).

Pathways
- Glycolysis decrease
- Glycogen synthesis decrease
- Glycogenolysis increase
- Gluconeogenesis increase
- Fatty acid synthesis decrease
- Fatty acid degradation increase

Molecules:
- Glycogen decrease
- Glucose increase- Fatty acids decrease
- Ketone bodies increase

Question 22

Describe metabolism (energy usage) in early starvation

Answer 22

Glucose is released from the liver due to gluconeogenesis and glycogenolysis -> for brain for oxidative phosphorylation

Other tissues are moving towards using fatty acids and ketone bodies for their energy, so there is mobilisation of FA from adipose tissue.
Glucose use falls as muscle switches to FA oxidation

Insulin drops causing GLUT4 expression by muscle to fall reducing glucose uptake

After around 12hrs 45% of resting energy from FA and 40% from glucose -> most to maintain brain activity

Question 23

Describe metabolism (energy usage) in intermediate starvation

Answer 23

Glycogen stores get depleted, there is increased lipolysis and ketogenesis.
Increased gluconeogenesis to maintain blood glucose.

Further starvation sees the kidney take over gluconeogenesis from the liver
- After 8 days B hydroxybutyrate is raised
So in moving from fed to starved state, we move from carb source of energy to fatty acid

Question 24

Describe metabolism (energy usage) in prolonged starvation

Answer 24

Production of ketone bodies increases with starvation, but after about 20 days β hydroxybutyrate (a ketone body) reaches plateaux.
Eventually the FA run out.
Then the body moves towards breaking down proteins from muscle in order to supply the brain in a last ditch attempt. By this time the brain would have moved to using ketone bodies, so that glucose demand falls to 40g/day.

There may still be generation of lactate and there will be generation of glycerol from TAGs which are gluconeogenic precursors (glycerol and AA oxidised)
Lactate will still be being recycled by the Cori cycle to make glucose

The movement from FA -> proteins is significant because the body cannot maintain breakdown of protein, eventually it will fail.

Question 25

Skeletal Muscle Transamination provides energy source from amino acids

Answer 25

Alanine formed from transamination of pyruvate and released into the blood is taken up by the liver where it can be converted to glucose.

The alpha-ketogluterate is a component of TCA cycle so can be fed into it

Question 26

Why is the urea cycle really important during starvation?

Answer 26

The urea cycle becomes very important when starving as muscle can use the carbon skeleton but cannot form urea.
The liver removed nitrogen through urea cycle (and produces pyruvate, can then be converted to glucose) and as you’re breaking down a lot of protein there is a lot of N to get rid of.