Lecture 9 - regulation of metabolism in fed and fasted states Flashcards
What is the definition of fed state (absorptive state)?
The 2-4 h period after ingestion of a normal meal
What happens to molecules in the fed state?
Plasma levels increase of CHO, AAs and TAGs. Islet tissue responds
The fed state is an …… period
anabolic period:
Increased syntehsis of TAG and glycogen to replenish fuel stores. Enhances teh synthesis of protein.
What happens to tissue to this (fed state) period?
All tissues use glucose.
The metabolic response during fed state is dominated by …
alterations in the metabolism of liver, adipose tissue, muscle and brain.
The flow of intermediates during metabolism in fed state is controlled by what 4 factors?
- ) Availability of substrates
- ) Allosteric activators and inhibitors
- ) Covalent modification of enzymes
- ) Synthesis of new enzyme molecules
What do the 4 factors that control metabolism during fed state ensure?
They ensure that fed state nutrient sare captured as glycogen, TAG and protein
How does the liver respond ot high blood glucose levels?
By increasing the phosphorylation of glucose by glucokinase which has a high kM for glucose.
why is glucose uptake by the hepatocytes not rate limiting?
Bc of an abundance in GLUT 2 glucose transporters.
What is the metabolic pathway for the breakdown of glucose in the well fed state?
- ) Glucose uptake by insulin independent GLUT-2 is driven by the rise in blood glucose
- ) The rise in glucose allows phosphorylation by glucokinase which has a high Km for glucose
- ) Glycogen synthase is activated covalently (dephosphorylated) and allosterically by glucose 6-P
- ) Glucose 6-P availability stimulates the PPP provinding NADPH for fatty acid synthesis
- ) Activation (dephosphorylation) of pyruvate dehydrogenase favors acetyl CoA production.
- ) Acetyl CoA carboxylase is activated covalently and allosterically by citrate
- ) TCA cycle inhibtion at isocitrate dehydrogenase allows use of acetyl CoA in fatty acid synthesis
- ) Glycolysis prrovides glycerol backbone for TAG synthesis
Overall:
Increased glucose transport
increased glycolysis
Increased PPP
Metabolic pathway in adipose tissue during absorptive state?
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.
What happens to skeletal muscles in fed state in regards to CHO, fat and AA metabolism?
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
What happens to the brain in the fed state?
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.
What are the inner tissue relationships during the fed state? What can dietary fat, protein and carbs be turned into?
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.
What are the sequence of events in fasting?
- 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.
What happens during early fasting?
Glycogen breakdown in the liver. LActate, pyruvate and alaine are diverted in glucose formation (gluconeogenesis)
What happens in body during fasting?
- 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
What is the cori cycle?
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.
What is the postabsorptive state?
after an overnight fast
What is the gluconeogenic phase?
early phase of starvation lasting until 2 or 3rd day of absolute starvation
What is the period adaptation to starvation?
The first 3 weeks where there will be hormonal changes, decrease in thyroid hormone which reduces overall metabolic rate
What is the period of adapted starvation ?
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.
What happens to lipid metabolism during fasting?
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.
What happens to liver in fasting in regards to CHO and Fat?
CHO - increase glycogen degredation, increased gluconeogenesis
Fat - increased FA oxidation, increased synthesis of ketone bodies.
What happens to adipose tissue in fasting in regards to CHO and Fat?
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.
What happens to the resting skeletal muscle in fasting?
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.
What happens to brain in fasting?
early fasting - uses glucose only
2-3 weeks later - ketone body concentration is increased and this becomes the predominant fuel source.
What happens to kidney in fasting?
- ) contains enzymes for gluconeogeneis and in late fasting 50% of gluconeogenesis occurs here
- ) counteracts acidosis that may be caused by elevated ketone bodies
- ) Glutamine that is released by muscles is taken up by kidney
- ) Picks up H ions from ketone bodies and excretes them as urine. This decreases acid load
