1. Integration of Metabolism Lecturer of Biochemistry
Dr.Manal Louis
Lecturer of Biochemistry

2. The Feed/Fast cycle 1- Well fed state ( the absorptive state )
2- Fasting state

3. 1- Well fed state ( the absorptive state )
-This is the 2-4 hr after absorption of meals
- All metabolites are increased: glucose, amino acids and TAG.
(the latter is a component of chylomicrons synthesized by intestinal mucosal cells).
-All tissues utilize glucose as a fuel.

4. 1- Well fed state ( the absorptive state )
-It is an anabolic phase due to
↑ I/G
b) Availability of circulating substrates.
c) Increase synthesis of TAG , glycogen and protein to replenish fuel stores.

5. Four major organs play a dominant role in fuel metabolism

6. A-The liver in well fed state
1-Concerning carbohydrate metabolism:
Hepatic metabolism is increased by the following mechanisms:
1- ↑ phosphorylation of glucose
2- ↑ glycogen synthesis
3- ↑ activity of HMP pathway
4- ↑ glycolysis
5- Activation of pyruvate dehydrogenase
6- ↓ gluconeogenesis

7. 1- ↑ phosphorylation of glucose
1) glucokinase:
-Is the most active enzyme in the fed state.
-Has a high Km→low affinity for glucose.
-Converts Glu→G6P
-Induced by insulin (elevated after meal) and repressed by glucagon ( elevated during fasting).

8. 2- ↑ glycogen synthesis
-By activation of glycogen synthase enzyme which is the key regulatory enzyme in conversion of G6P→glycogen -is activated by dephosphorylation (by insulin), and by the increased level of glucose [ both available in the fed state].

9. 3- ↑ activity of HMP pathway
- By the increased availability of G6P in the well fed state. - By insulin induction of both dehydrogenases of the pathway - By the active use of NADPH in hepatic lipogenesis

10. By activation of the rate limiting enzymes of glycolysis

11. 5-Activation of pyruvate dehydrogenase
-pyruvate enters the mitochondria and is converted to acetyl coA by PDH. -PDH is active when substrates are available and by dephosphorylation -PDHK is inhibited by pyruvate - Fate of acetyl CoA: FA synthesis or energy production in TCA cycle

12. 6- ↓ gluconeogenesis
1)Acetyl CoA is used for FAs synthesis→↓its level → inhibition of pyruvate carboxylase 2) inhibition of fructose 1,6-bisphosphatase

13. 2- Concerning fat metabolism
Synthesis of fatty acids are elevated due to:
1-Citrate lyase is stimulated, which cleaves cytoplasmic citrate into oxaloacetate and acetyl CoA.
2-Increased the activity of acetyl-CoA carboxylase both by dephosphorylation and by the presence of its allosteric activator citrate forming more malonyl- CoA.

14. 2- Concerning fat metabolism
3-An increase in activity of fatty acid synthase.
4-Availability of substrates (acetyl CoA and NADPH derived from the metabolism of glucose).

15. Increased TAG synthesis
1- Acyl CoA is available from
A- denovo synthesis of from acetyl CoA.
B- hydrolysis of TAG component of chylomicron remnants.
2- Glycerol 3-phosphate
(the backbone for TAG) is provided by glycolysis.

16. 3-Amino acid metabolism
1- ↑ AA degradation
2- ↑ protein synthesis

17. 1- ↑ AA degradation -In the absorptive state there is excess AAs :
A) Released into the blood for all tissues to use in protein synthesis.
B) Deaminated with the resulting carbon skeleton being degraded by the liver to pyruvate, acetyl CoA or TCA intermediates.
- Branched chain AAs pass through the liver unchanged and are metabolized by muscles.

18. 2- ↑ protein synthesis
To replace any proteins that may have been degraded during the previous postabsorptive period.

20. B- Adipose tissue in well fed state
1) Carbohydrate metabolism:
-↑ glucose transport by insulin-dependent GLUT-4:
↑insulin results in ↑influx of glucose into adipocytes.
- ↑ glycolysis:
Source of glycerol phosphate for TAG synthesis.
↑ activity of HMP pathway:
Source of NADPH+H used in denovo synthesis of FAs.

21. 2- Fat metabolism: - ↑ synthesis of FAs - ↑ synthesis of TAGs
- ↓ degradation of TAGs
(increase in I /G inhibits the hormone-sensitive lipase enzyme which can hydrolyze TAG )

23. C- Skeletal muscles in well fed state
A) Resting Skeletal muscles
1) Carbohydrate metabolism:
- ↑ glucose tranport by insulin-dependent GLUT-4,
its phosphorylation by hexokinase
its oxidation to provide energy
- ↑ glycogen synthesis due to ↑ G-6-P

24. 2- Fat metabolism in resting skeletal muscles:
↑uptake of FAs
(Fatty acids are released from VLDL & chylomicrons by the action of lipoprotein lipase enzyme)
FAs are 2ry source of energy
Glucose is the primary source of energy.

25. 3- AA metabolism in resting skeletal muscles:
- ↑ protein synthesis:
due to uptake of AA after a meal containing protein
- ↑ uptake of branched chain AA:
Muscle is the principal site for their degradation

27. Source of energy for active skeletal muscles in well fed state
Slow-twitch muscle fibers:
-Aerobic oxidation of glucose until glycogen stores are degraded 1-3 hours and then FAs.
2) Fast-twitch muscle fibers:
-Anaerobic glycolysis in case of high-intensity exercise

28. Source of energy for heart muscles in well fed state
1) Fetal cardiac muscle: glucose 2) In postnatal period: β-oxidation of FAs 3) In adults: FAs are the major fuel for cardiac myocytes

29. D- Brain in well fed state
1) Carbohydrate metabolism:
-There is no significant glycogen storage.
-Therefore the brain depends exclusively upon glucose oxidation to obtain its energy requirement.

30. 2- Fat metabolism in brain
-There is no significant TAG storage.
-There is no FA oxidation, as fatty acids cannot cross the blood-brain barrier.

32. B) Fasting state -The blood levels of nutrients are decreased
-Insulin level is decreased (↓ I / G).

33. A-The liver in fasting state
1-Concerning carbohydrate metabolism:
- ↑ glycogen degradation
Increased glucagon secretion inhibits glycogen synthase and stimulates glycogen phosphorylase in the liver.
G-6-P is acted upon by G-6-phosphatase producing glucose which can be utilized by most tissues.
The liver glycogen is exhausted hours of fasting.

34. - ↑ gluconeogenesis:
It begins 4-6 hr after the last meal AND is fully active when liver glycogen is depleted.
the gluconeogenic substances are:
1- lactate (the earliest)
2-Glycerol from lipolysis in adipose tissue (the 2nd ).
3-Propionate.
4- gluconeogenic AAs

35. Key enzymes of gluconeogenesis are activated as follows:
1- fructose 1,6-bisphosphatase by a drop of its allosteric inhibitor fructose 2,6-bisphosphate. 2- phosphoenolpyruvate carboxykinase by induction by glucagon. 3- pyruvate carboxylase by increase of its allosteric activator acetyl CoA.

36. The presence of glucose 6-phosphatase in the liver
Glucose from both glycogenolysis and gluconeogenesis

37. 2- Fat metabolism in liver during fasting
↑ FAs oxidation:
-An elevated glucagon level stimulates lipolysis (in adipose tissue) by activation of the hormone-sensitive lipase (via ↑ cAMP).
-A rise in the level of free fatty acids
-Uptake & Oxidation of FFA by the liver is accelerated producing acetyl CoA, exceeding the rate of their utilization in TCA cycle

38. Inactivation of acetyl CoA carboxylase by phosphorylation
Fall in malonyl CoA Removal of inhibitory effect on carnitine palmitoyl transferase Β-oxidation NADH and ATP required by the liver for gluconeogenesis

39. ↑synthesis of ketone bodies
Sources of acetyl CoA used in ketogenesis:
1-Oxidation of FAs
2-Ketogenic & mixed AAs
The liver is unique in being able to synthesize and release KBs (3-hydroxybutyrate) for use by peripheral tissues NB
The liver cannot use KBs as a fuel

40. Why ketone bodies are important ?
1- can be used as fuel by most tissues including brain . 2- they reduce the need for gluconeogenesis from AA carbon skeleton. 3- ketogenesis releases CoA ensuring its availability for continued fatty acid oxidation.

42. B- Adipose tissue in fasting state
-An elevated glucagon level and epinephrine & norepinephrine released from sympathetic nerve endings →
activation of the hormone-sensitive lipase →
stimulates lipolysis releasing FFAs and glycerol

43. FFAs bound to albumin in blood
Transported to a variety of tissues for use as fuel, also oxidized to acetyl CoA which enters TCA cycle

44. Used as a gluconeogenic precursor by the liver
glycerol
Used as a gluconeogenic precursor by the liver

45. C- Skeletal muscles in fasting state
1-Concerning carbohydrate metabolism:
-↓glucose uptake due to decrease number of insulin-dependent GLUT-4
-↓ utilization
due to low level of insulin

46. 2-Concerning lipid metabolism:
- During the first 2 weeks of fasting
Muscles use FAs from adipose tissue & KBs from the liver as fuels.
- After 3 weeks
Oxidizes FAs almost exclusively→↑KBs

47. 3-Concerning protein metabolism:
- There is breakdown of muscle protein ( proteolysis ) providing AAs for gluconeogenesis in the liver producing glucose
-By several weeks of fasting
Proteolysis ↓ due to ↓ the need of brain for glucose which begin to use KBs as a source of energy

48. Fuels used as source of energy for skeletal muscles in fasting
1- Resting muscle: FAs 2- Exercising muscle: glycogen 3- During intense exercise: FAs provided from lipolysis

49. Brain in fasting
-During the first few days of fasting , the brain uses glucose exclusively
-In prolonged fasting
( more than 2-3 weeks ) it uses KBs.

50. Role of kidney in long-term fasting
1- Expression of enzymes of gluconeogenesis Glucose 6 phosphatase. 2- Compensation for acidosis resulting from ketogenesis

51. How kidney compensates for acidosis resulting from ketogenesis
1- uptake of glutamine coming from metabolism of branched chain AAs 2- Renal glutaminase and glutamate dehydrogenase produce: A) α-KG which enters TCA cycle. B) Ammonia which picks up H+ coming from KB dissociation and excretes it in urine in the form of NH4+

52. Factors which determine the duration of survival of a fast
1) The amount of adipose tissue Supplies the body with its major source of fuel 2) Body protein level: essential for function of vital organs and immune response 3) Deprivation of vitamins and minerals 4) Lack of ATP 5) Electrolyte composition of the blood

53. Q) Insulin will activate one of the following enzymes:
a. phosphoenol-pyruvate carboxykinase b. HMG CoA lyase c. lipoprotein lipase d. hormone-sensitive lipase

54. Q) Under prolonged starved state, the primary source of energy for brain is:
A.Glucose b. ketone bodies c. lactate d. fatty acids

55. Q) During starvation, when ketone bodies are increased they will : a
Q) During starvation, when ketone bodies are increased they will : a. inhibit further proteolysis from muscles b. inhibit further glycogenolysis from liver c. all of the above d. stimulate further lipolysis from adipose tissue

56. Q) Although there is no storage form of amino acids, the body can utilize muscle proteins as a source of amino acids only for energy production in prolonged starvation. Answer: True False

57. Q) In well-fed state, the following enzymes are active EXCEPT: a
Q) In well-fed state, the following enzymes are active EXCEPT: a. pyruvate dehydrogenase. b. Glucokinase c. HMG CoA reductase d. fructose – 2,6 bisphosphatase

58. Q) The brain can utilize the following as a source of energy EXCEPT: a
Q) The brain can utilize the following as a source of energy EXCEPT: a. glucose b. ketone bodies c. carbon skeleton of some amino acids d. fatty acids

59. Q) Brain has a high content of triacylglycerol store that can be hydrolyzed during prolonged starvation
Answer:
True
False