Integration of metabolism Flashcards
Metabolic specialisation of organs and tissues
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
These needs and the way they use these particular metabolites may change with changing circumstances such as disease state
These changes may affect how one organ interacts with another
Brain
what does it require? around?
what is half of this energy used for? why?
what does the brain lack? hence what does it need? which one does it use? why?
when is there a danger point?
what can we use in a dire state?
The brain requires a lot of glucose, usually around 100-120g daily.
Over half of the energy consumed is used for Na+/K+ transport to maintain the membrane potentials of neurones and also for synthesis of neurotransmitters.
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).
Cardiac Muscle
what is it dependent on?
what does it have little stores of?
main source of energy? supplied by? followed by? how?
why is this energy source used?
Cardiac muscle is dependent on aerobic respiration
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 are used is because it yields a much greater amount of ATP
lactate -> pyruvate -> acetyl CoA
Adipose Tissue
what is this the main reserve of?
what makes most of these?
overall where do get most of our FA? (2)
Adipose tissue is the main reserve for 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.
Kidney
major role?
why does kidney use up a lot of energy?
during starvation how does the kidney help?
The major role of the kidney is to produce urine, with the plasma being filtered up to 60x daily, with only a small volume of urine being produced.
This is through water-soluble material largely being reabsorbed to prevent loss.
The kidney although only 0.5% of body mass consumes 10% of the body’s energy – mainly for active transport
During starvation the kidney may contribute half of the blood glucose through gluconeogenesis.
Liver
what does the liver provide energy for?
what does the liver take energy from?
what 2 specific enzymes does liver have for glucose?
which enzyme is active when glucise levels are high?
The liver plays a central role in regulating metabolism, for
• Carbohydrates
• Fatty acids
• Amino acids
Most compounds absorbed by the gut pass through the liver, the liver also provides fuel for other tissues such as brain, muscle and other peripheral organs.
The liver itself takes its energy from α-ketoacids (α-ketogluterate, pyruvate, oxaloacetate)
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.
Control of Blood Glucose by Liver Metabolism
how is glucose transported into liver? what doesnt regulate this?
what happens to glucose immediately?
what happens if glucose levels are low? enzyme involved?
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 also allowing conversion of G6P -> glucose in gluconeogenesis/glycogenolysis which can be transported out by GLUT-2.
GK
glucose glut 2 G6P glycogen
G6P-ase
Muscle Glucose Metabolism
glucose transporter in muscle?
what happens to glucose once inside?
what does msucle not have? hence what is the fate of the G6P?
what is glucose uptake by muscle dependent on?
Muscle has a different glucose transporter, the GLUT-4. 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.
So, muscle uses energy through oxidation of glucose but also stores it, but only for its own use.
Glucose is mobilised from glycogen in exercise.
Glucose uptake by Glut-4 is insulin-dependent
Glycolysis of the G6P is a rapid source of ATP
Low free [glucose] in cell
HK
glucose/insulin –> glut 4 –> G6P glycogen
OR G6P –> glycolysis
Interchange of Nutrients Between Organs, to keep appropriate energy supply to tissue
Topics now to be looked at
- Metabolic difference between running 100m and running a marathon
- Fed and unfed state (how body adapts to amount of nutrients available)
- Lifestyle
Fuel for a Sprint or Marathon
what directly powers myosin for contraction?
muscle atp stores? hence for a sprint what is ideal?
what 4 things power a 100m sprint?
what does fuel for a marathon require? why?
what is beneficial about marathon? how does metabolism change? why?
so what is used durinf sprints? marathon?
does marathon generate lactate?
what else is generated and fed to liver for glucose?
2 reasons for glucose?
ATP in both cases directly powers myosin for contraction of muscle
• Conversion of chemical energy to movement
However, muscle ATP stores are small, as well as this all chemical reactions take time so for a 9 second burst this is very short when we need that ATP instantly.
A 100m sprint is powered by 1. ATP stores --> used quick 2. Glycolysis --> anaerobic 3. Glycogen --> for a brief time 4. Creatine phosphate Muscle contains creatine phosphate which can react with ADP to give ATP and creatine.
Sprint is an anaerobic activity –> Anaerobic breakdown of glycogen stores gives lactate and a fall in pH
Fuel for a Marathon
Marathon running requires co-operation between muscle, liver and adipose tissue. This is because the amount of ATP required exceeds that are stored by the muscle since it needs to be generated over a longer period of time.
However because time is longer, we can use a more efficient way of getting that ATP = aerobic respiration
As said because complete oxidation is slow, we can do this in a marathon. For a marathon we need 150 moles ATP, but body glycogen will only provide 103 mole ATP
• But by end we will still have about half our glycogen store left as body switches to fat metabolism
Fats are a large source of ATP; the metabolism is slower than glycogen and 10x slower than creatine phosphate.
- >
Sprinter = uses glucose
- >
Marathon runner = use fatty acids -> generate Acetyl CoA -> TCA, some protein may also be broken down as you need to maintain blood glucose so brain has enough.
Even in a marathon there will be some generation of lactate
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
Feast and Famine
Fed state - pathways + molecules
what is maintained in fed state? hence what will happen to excess calories?
in terms of pathways what happens? (6)
in terms of molecules what happens? (4)
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.
So in the fed state we will see:
With regards to pathways:
o Glycolysis increase
o Glycogen synthesis increase
o Glycogenolysis decrease (don’t want to produce glucose when sufficient levels in blood)
o Gluconeogenesis decrease (don’t want to produce glucose when sufficient levels in blood)
o Fatty acid synthesis increase
o Fatty acid degradation decrease
With regards to molecules: o Glycogen increase o Glucose decrease o Fatty acid increase o Ketone bodies decrease
What about when we stop eating?
Post-absorptive phase - pathways + molecules
when does this occur? (2)
what is the main energy source to restablish glucose levels?
hence what activity increases and why?
in terms of pathways what happens? (6)
in terms of molecules what happens? (4)
When you stop eating there is almost 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 must be met.
Post-absorptive phase
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.
Reactions in post-absorptive phase in liver Pathways o Glycolysis decrease o Glycogen synthesis decrease o Glycogenolysis increase o Gluconeogenesis increase o Fatty acid synthesis decrease o Fatty acid degradation increase
Molecules: o Glycogen decrease o Glucose increase o Fatty acids decrease o Ketone bodies increase
Early Starvation (4-24 hrs.)
where is glucose released from? due to? (2) and why?
what do other tissues move towards for energy source? hence what?
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
After around 12hrs 45% of resting energy from FA and 40% from glucose -> most to maintain brain activity.
Intermediate Starvation (1-20 days)
what is depleted? what proceses are increased and why?
what can take over gluconeogenesis from liver?
if we prolong this, what can happen?
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
So, in moving from fed to starved state, we move from carb source of energy to fatty acid, then for prolonged we will start breaking down structural proteins.
Prolonged Starvation (over 3 weeks)
what happens after 20 days?
what does the body move towards?
what does brain use at this point?
what 2 things may be generated still? what are these used for?
why is this metabolic movement significant?
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.
Lactate will still be being recycled by the Cori cycle
The movement from FA -> proteins is significant because the body cannot maintain breakdown of protein, eventually it will fail.
