Lecture 37 - Intergraton of whole body metabolism

Question 1

Unique metabolic profile - Brain (5)

Answer 1

Required a lot of glucose (100-120g daily).
Over half of the energy is used for Na+/K+ transport to maintain membrane potentials of neurones for synthesis of neurotransmitter.
Brain lacks energy source. In order for it to use glucose, glucose transporters (GLUT 3). Transporter has a Low Km, and is saturated under most conditions.
Danger points when plasma glucose drops below 2.2 mM.
In case of emergency, FA and ketone bodies are used.

Question 2

Unique metabolic profile - Cardiac muscle (4)

Answer 2

Dependent on aerobic respiration.
Deprivation = Angina.
Little/No glycogen stores, main energy source is FA (yields large amounts of ATP), lactate, ketone bodies supplied by liver.
Lactate—> Pyruvate —> Acetyl CoA

Question 3

Unique metabolic profile - Adipose tissue (3)

Answer 3

Main reserve for triacylglyceride storage.
Reservoir metabolic energy in form of TG 70kg man 15kg of TG.
Liver makes FA we get most from our diet, delivered by chylomicrons.

Question 4

Unique metabolic profile - Kidney (3)

Answer 4

Major role is to produce urine, plasma filtered x60 daily, with only a small volume of urine being produced, water soluble material largely reabsorbed to prevent loss.
Kidney makes up 0.5% of body mass and consumes 10% of the body’s energy (mainly for active transport).
During starvation the kidney may contribute half of the blood glucose through gluconeogenesis.

Question 5

Unique metabolic profile - Liver (5)

Answer 5

Central role in regulating metabolism - carbohydrates/FA/aa.
Most compounds absorb by gut pass through the liver.
Liver provides fuel for tissues such as brain, muscle and other peripheral organs.
Liver takes its energy from a-ketoacids (a-ketogluterate, pyruvate, oxaloacetate).
Liver uses glucokinase enzyme for phosphorylating glucose, has a high Km, so only maximally active when glucose conc is high, it’s there to keep blood glucose constant.

Question 6

Hexokinase and Glucokinase activities ()

Answer 6

Hexokinase -

Glucokinase - High Km,

Question 7

Overview (3)

Answer 7

Pathways within cells interact, calls within tissues interact and organs within the body.
Different organs and tissues have different needs, they may use the same molecule but in different ways (e.g. on using it to store, other for energy source, or to generate a new molecule - biosynthesis).
The needs and way they use these particular metabolites may change with changing circumstances such as diseased state. This changes how organs interact with one another.

Question 8

Unique metabolic profile - Brain (6)

Answer 8

Requires alot of glucose 100-120g daily. Half of which is used by Na+/K+ to maintain membrane potentials in neurones (by synthesising neurotransmitters).
Lacks energy stores, so in order for it to use glucose a glucose transport (GLUT3) is required. It has a low m and is maximally active at conc of glucose seen at any time. So it is not affected by fluctuations in glucose, so brain won’t be starved of main energy source.
Danger point is when plasma glucose is below 2.2 mM.
FA, KB (ketone bodies) are used if there is a lack of glucose.

Question 9

Unique metabolic profile - Cardiac muscle (5)

Answer 9

Aerobic respiration.
Deprive = Angina.
Little/no glycogen stores. main source of energy is FA supplied by liver. Followed by ketone bodies and lactate.
Lactate --> pyruvate --> acetyl CoA.
FA yields a greater amount of ATP.

Question 10

Unique metabolic profile - Adipose Tissue (3)

Answer 10

Main reserve for triacylglyceride storage.
70kg man, 15kg of TG.
We get most FA from diet which is delivered by chylomicrons.

Question 11

Unique metabolic profile - Kidney (3)

Answer 11

Main role is to produce urine.
Plasma filtered 60x daily, and a small volume of urine produced - as water-soluble material is being reabsorbed to prevent loss.
Kidney 0.5% of body mass consumes 10% of the body’s energy - mainly for active transport.
During starvation kidney contributes half of blood glucose through gluconeogensis.

Question 12

Unique metabolic profile - Liver (5)

Answer 12

Regulates metabolism for: Carbohydrates, FA, AA.
Most compounds absorbed by gut pass through the liver.
Liver provides fuels for other tissues e.g. brain, muscle, peripheral organs.
Liver takes energy from from α-ketoacids (α-ketogluterate, pyruvate, oxaloacetate).
Uses glucokinase enzyme, high Km and maximally active when glucose conc is elevated.

Question 13

Control of blood glucose by liver metabolism (3)

Answer 13

Glucose transported into hepatocytes via GLUT2 (NOT insulin sensitive).
Glucose is PHOSPHORYLATED to G6P [glucokinase].
G6P (from glycogen breakdown / gluconeogenesis) converted to glucose [glucose-6-phosphatase] and transported out of the cell into blood by GLUT 2.

Question 14

Muscle glucose metabolism (4)

Answer 14

GLUT 4
Glucose –> G6P [hexokinase, low kM (0.1mM ) so equilibrium towards G6P], allowing low glucose concentrations into the cell.
Muscle does not have [glucose-6-phosphatase] so can’t convert G6P to glucose, instead G6P is used to synthesise glycogen or used in glycolysis.
Muscle uses energy through oxidation of glucose, but also stores it for its own use.

Question 15

Metabolic difference between running 100m and running a marathon - Sprint (8)

Answer 15

A 100m sprint is powered by
ATP stores  used quick
Glycolysis  anaerobic
Glycogen  for short time
Creatine phosphate 

Muscle contains creatine phosphate which can react with ADP to give ATP and creatine.
5-6 s of energy reserves.
Sprint is an anaerobic activity. Anaerobic breakdown of glycogen stores gives lactate and a fall in pH.
Activity of glycogen phosphorylase enhanced by phosphorylation whereas glycogen synthase inhibited.

Question 16

Metabolic difference between running 100m and running a marathon - Marathon (8)

Answer 16

Requires co-operation between muscle, liver and adipose tissue - amount of ATP required (needs to be generated over a longer period of time) exceeds that stored by the muscle.
Aerobic respiration.
Complete oxidation is slow and is used in marathons.
Marathon requires 150 moles ATP, body glycogen provides 103 moles (by the end we still have our glycogen store left. as body switches to fat metabolism).
More efficient to use fat and glycogen, regulated by acetyl CoA from fat which regulates glucose in TCA.

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).

Alanine is produced when a protein is degraded and even lactate (anaerobic respiration) will be produced –> pyruvate. These are the transported to the liver where they enter a 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.
During exercise glycolysis exceeds the capacity of the TCA cycle, pyruvate converted to lactate and transported to liver Cori cycle.

Question 17

FED state (5)

Answer 17

Blood glucose maintained.
Brain will take what it needs.
When there is excess calorific intake (though carb), converted to FA stored in adipocytes OR muscle where it can be stored as fat or glucose as glycogen.
AA - used for PS/keto acids when in excess.
VLDLs - Delivers fat to muscles.
Resting muscle - Uses FA as source of energy.
Adipose tissue - Excess glucose stored as FA in adipocytes or as glycogen in muscle.

Question 18

FED State table (10)

Answer 18

On flashcard

Question 19

What about when we stop eating?

Answer 19

An immediate drop in consumption of energy, in a healthy individual by 40% if you restrict your diet by a third. But there is still an energy requirement that has to be met.

Question 20

Early starvation (4-24 hrs) (5)

Answer 20

Glucose released from liver due to gluconeogenesis and glycogenolysis - for brain, oxidative phosphorylation.
Tissue move towards using KB and FA for energy, so mobilisation of FA from adipose tissue.
Glucose use falls as muscle switches to FA oxidation.
Insulin drops so GLUT 4 expression (in muscle) falls, reducing glucose uptake.
After 12 hrs 45% of resting energy from FA, 40% from glucose (maintain brain activity).

Question 21

Intermediate Starvation (1-20 days) (6)

Answer 21

Glycogen stores are depleted, increased lipolysis and ketogenesis.
Increased gluconeogenesis to maintain blood glucose.
60 hrs FA account for75% energy provision.
After 8 days days β hydroxybutyrate is raised 50-fold.
Kidney takes over gluconeogenesis from the liver.
So from Fed to starved state, we move from car source of energy to FA, then for prolonged we start breaking down structural proteins.

Question 22

Post-absorptive phase (5)

Answer 22

Post-absorptive phase is several hours after the last meal or if you restrict your diet.
The main energy source to re-stablish the low blood glucose levels is glycogen. Hence there will be an increase in phosphorylase a activity to increase glycogen breakdown.
As the ketone body concentration increases so does the use by the brain.
Adipocytes will release FA and glycerol.

Question 23

Prolonged Starvation (over 3 weeks) (9)

Answer 23

Production of KB increases = starvation increases.
After 20 days β hydroxybutyrate (a ketone body) reaches plateaux.
Eventually the FA run out.
Body then moves towards breaking down proteins from muscle to supply brain in last-ditch attempt.
Brain moved on to use KB, so glucose demand falls to 40g/day.
May still be generate of lactate/glycerol from TG, which are still gluconeogenic precursors.
Lactate - Cori cycle.
Glycerol/AA - Oxidised.

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

Question 24

Skeletal Muscle Transamination provides energy source from amino acids (3)

Answer 24

Pyruvate transaminated into alanine (released into blood and taken up by liver to be made into glucose).
The alpha-ketogluterate is a component of TCA cycle so can be fed into it.

Urea cycle - muscle can use the carbon skeleton but cannot form urea. The liver removes 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.

Question 25

Starvation - summarised (6)

Answer 25

 First body tries to maintain glucose for brain from glycogen breakdown.
 Gluconeogenesis can help maintain glucose levels (through glycerol and pyruvate).
 Fatty acids generated from TAG breakdown converted to ketone bodies, brain starts to use these through oxidative phosphorylation.
 Some fatty acids broken down and used by the liver itself.
 Finally, breakdown of skeletal muscle, broken into amino acids. Some converted to alanine other as free AA.
 This is to try to generate a glucose conc. the body can use.