Lecture 9 - regulation of metabolism in fed and fasted states

Question 1

What is the definition of fed state (absorptive state)?

Answer 1

The 2-4 h period after ingestion of a normal meal

Question 2

What happens to molecules in the fed state?

Answer 2

Plasma levels increase of CHO, AAs and TAGs. Islet tissue responds

Question 3

The fed state is an …… period

Answer 3

anabolic period:

Increased syntehsis of TAG and glycogen to replenish fuel stores. Enhances teh synthesis of protein.

Question 4

What happens to tissue to this (fed state) period?

Answer 4

All tissues use glucose.

Question 5

The metabolic response during fed state is dominated by …

Answer 5

alterations in the metabolism of liver, adipose tissue, muscle and brain.

Question 6

The flow of intermediates during metabolism in fed state is controlled by what 4 factors?

Answer 6

1. ) Availability of substrates
2. ) Allosteric activators and inhibitors
3. ) Covalent modification of enzymes
4. ) Synthesis of new enzyme molecules

Question 7

What do the 4 factors that control metabolism during fed state ensure?

Answer 7

They ensure that fed state nutrient sare captured as glycogen, TAG and protein

Question 8

How does the liver respond ot high blood glucose levels?

Answer 8

By increasing the phosphorylation of glucose by glucokinase which has a high kM for glucose.

Question 9

why is glucose uptake by the hepatocytes not rate limiting?

Answer 9

Bc of an abundance in GLUT 2 glucose transporters.

Question 10

What is the metabolic pathway for the breakdown of glucose in the well fed state?

Answer 10

1. ) Glucose uptake by insulin independent GLUT-2 is driven by the rise in blood glucose
2. ) The rise in glucose allows phosphorylation by glucokinase which has a high Km for glucose
3. ) Glycogen synthase is activated covalently (dephosphorylated) and allosterically by glucose 6-P
4. ) Glucose 6-P availability stimulates the PPP provinding NADPH for fatty acid synthesis
5. ) Activation (dephosphorylation) of pyruvate dehydrogenase favors acetyl CoA production.
6. ) Acetyl CoA carboxylase is activated covalently and allosterically by citrate
7. ) TCA cycle inhibtion at isocitrate dehydrogenase allows use of acetyl CoA in fatty acid synthesis
8. ) Glycolysis prrovides glycerol backbone for TAG synthesis

Overall:
Increased glucose transport
increased glycolysis
Increased PPP

Question 11

Metabolic pathway in adipose tissue during absorptive state?

Answer 11

Adipocytes contain insulin sensitive GLUT-4 and so fat stored in adipose tissue is derived from dietaryr fatty acids made in hte liver and packaged as TAG in VLDL. LPL in the capillaries degrade the TAG releasing fatty acids.

Increased TAG storage.

Question 12

What happens to skeletal muscles in fed state in regards to CHO, fat and AA metabolism?

Answer 12

CHO:
increase glucose transport
increase in glycogen synthesis

Fat:
FAs from chylomicrons by lipoprotein lipase

AA metabolism:
increase in protein synthesis
Increaase in uptake of BCAA

Question 13

What happens to the brain in the fed state?

Answer 13

Glut-1 in the brain is insulin insensitive and during fed state the brain solely uses glucose as energy.

It lacks significant stores of TAGs and FAs circulating in the blood and they do little contribution to energy of the brain because they are boudn to albumin which does not cross the blood brain barrier efficiently.

Question 14

What are the inner tissue relationships during the fed state? What can dietary fat, protein and carbs be turned into?

Answer 14

If the caloric intake exceeds caloric expenditure then all three will be turned into triacyglycerol which will be stored in adipose tissue.

Note that the protein and carbs will turn into tri at the liver then trasnported to the adipose tissue wheras the fat will turn into tri at the adipose tissue.

Question 15

What are the sequence of events in fasting?

Answer 15

• Plasma levels of glucose and amino acids and TAG will fall
• This will trigger a decline in insulin secretion
• There will be a simultaneous increase in glucagon secretion
• System will enter a catabolic state
• This will initiate mobilisation of potential fuel sources among the liver, adipose tissue, muscle and brain with two priorities:
  1. ) need to maintain adequate plasma levels of glucose in order to sustain energy metabolism in the brain, RBCs and other glucose requiring tissues

2.) Need to mobilise FAs from adipose tissue and the synthesis and release of ketone bodies from the liver to supply energy to all other tissues.

Question 16

What happens during early fasting?

Answer 16

Glycogen breakdown in the liver. LActate, pyruvate and alaine are diverted in glucose formation (gluconeogenesis)

Question 17

What happens in body during fasting?

Answer 17

• No fuel from the gut
• Little glycogen left in the liver after 10-12 hours fasting
• The body is dependent on hepatic gluconeogenesis from lactate, glycerol and alanine
• the cori cycle becomes important

Question 18

What is the cori cycle?

Answer 18

Essentially, glucose that is formed from lactate and alanine by the liver only replaces that which was converted to lactate and alnine by peripheral tissue in the first place.

Question 19

What is the postabsorptive state?

Answer 19

after an overnight fast

Question 20

What is the gluconeogenic phase?

Answer 20

early phase of starvation lasting until 2 or 3rd day of absolute starvation

Question 21

What is the period adaptation to starvation?

Answer 21

The first 3 weeks where there will be hormonal changes, decrease in thyroid hormone which reduces overall metabolic rate

Question 22

What is the period of adapted starvation ?

Answer 22

3 weeks onwards and will continue unless refed. Length of survival depends on fat stores and when fat stores are depleted, thebody will use protein as energy and quickly death will come. Death is usually becuase respiratory msucles will not be able to clear the lungs properly and pneumonia will set in.

Question 23

What happens to lipid metabolism during fasting?

Answer 23

Levels of fatty acids in blood is raised and this is used as energy for the heart and muscle.

liver - fatty acid oxidation provides ATP for gluconeogenesis, ketone bodies are formed and released. When levels are high they supply the brain, but do not totally replace glucose. Ketone bodies prevent muscle wasting by decreasing protein degredation.

pancreas - Releases glucagon

thyroid - reduced production of active thyroid hormone and reduces basal energy requirments by 25%. Makes weight loss difficult.

Question 24

What happens to liver in fasting in regards to CHO and Fat?

Answer 24

CHO - increase glycogen degredation, increased gluconeogenesis

Fat - increased FA oxidation, increased synthesis of ketone bodies.

Question 25

What happens to adipose tissue in fasting in regards to CHO and Fat?

Answer 25

CHO - Glut 4 is depressed and so there is reduced glucose uptake which influences FA and TAG synthesis

Fat - increased degredation of TAG and increase release of FAs. Decreased uptake of FAs.

Question 26

What happens to the resting skeletal muscle in fasting?

Answer 26

It uses FAs as fuel source and exercising muscle uses glycogen stores. Intense exercise, lactate formed from glycogen (anerobic). When all these sources gone, TAG from adipose tissue becomes the dominant fuel source.

Question 27

What happens to brain in fasting?

Answer 27

early fasting - uses glucose only

2-3 weeks later - ketone body concentration is increased and this becomes the predominant fuel source.

Question 28

What happens to kidney in fasting?

Answer 28

1. ) contains enzymes for gluconeogeneis and in late fasting 50% of gluconeogenesis occurs here
2. ) counteracts acidosis that may be caused by elevated ketone bodies
3. ) Glutamine that is released by muscles is taken up by kidney
4. ) Picks up H ions from ketone bodies and excretes them as urine. This decreases acid load