MEH 3 - Glycogen + Fat (energy storage)

Question 1

Which tissues have an absolute requirement for glucose as an energy store?
What is a normal blood glucose concentration + what enables glucose to be kept stable?

Answer 1

• RBC’s, neutrophils, innermost cells of kidney medulla, Lens of the eye.
• 5mmol/L - glucose can be stored as glycogen. Glycogen is stored as granules, both in the muscle and liver.

Question 2

Describe the structure of glycogen - including the bonds linking adjacent monomers and branch points.

Answer 2

• Glycogen is a polymer of glucose residues, with chains branching off at various points.
• These chains originate from a dimer of the protein -glycogenin (primer at the core of the structure).
• Glucose residues linked via a,1-4 glycosidic bonds w/branch points at every 8-10 residues linked via a,1-6 glycosidic bonds.

Question 3

Describe the process of glycogenesis (glycogen synthesis)

Answer 3

1) Glucose + ATP –> G6P (via hexokinase)
2) G6P –> G1P (via phosphoglucomutase)
3) G1P –> UDP glucose + PPi (via G1P uridyltransferase)
4) Glycogen + UPD glucose –> glycogen (n+1 residues) + UDP

• Essentially seeing UDP glucose incorporated into existing glycogen polymer via glycogen synthase (for a,1-4 bonds) and branching enzyme (for a,1-6 bonds).

Question 4

Describe the process of glycogenolysis (glycogen degradation)

Answer 4

1) Glycogen + Pi –> G1P + glycogen (n-1 residues) - via glycogen phosphorylase or debranching enzyme
2) G1P –> G6P (via phosphoglucomutase)
3) G6P used for glycolysis in muscle or released into blood by the liver for use by other tissues.

Question 5

What is the role of glycogen stores in the liver and muscle respectively?

Answer 5

Liver = G6P converted into glucose by G6-phosphotase. Glucose exported into the blood. Liver glycogen is therefore a buffer of blood glucose levels.

Muscle = Lacks G6-phosphotase. G6P enters glycolysis for energy production.

Question 6

What are the rate-limiting enzymes of glycogen synthesis and degradation?
How do hormones regulate liver glycogen metabolisation?

Answer 6

• Synthesis = glycogen synthase. Degradation = glycogen phosphorylase.
  1) Glucagon + adrenaline phosphorylate both enzymes, to increase activity of phosphorylase and reduce activity of synthase - thus mobilising glycogen for energy (during flight or fight response)
  2) Insulin dephosphorylates both enzymes, to decreases activity of phosphorylase and increase activity of synthase - thus storing glucose as glycogen.

NB: glucagon has no effect on muscle glycogen as they dont have correct receptors.

Question 7

Give 2 glycogen storage diseases + how they arise.

What are the consequences of such diseases?

Answer 7

1) Von Gierke’s disease - G6P-phosphotase deficiency
2) McArdle’s disease - muscle glycogen phosphorylase deficiency

• Excess glycogen storage leads to tissue damage, hypoglycaemia + poor exercise tolerance. (NB - these are inherited deficiencies).

Question 8

When + where does gluconeogenesis occur?
What are the 3 major precursors of gluconeogenesis?
What are the 3 major enzymes in gluconeogenesis?

Answer 8

• Beyond 8 hours of fasting, liver glycogen stores deplete - alternative source of glucose required
• In the liver, but to a lesser extent in the kidney cortex
• 1) Lactate (from anaerobic glycolysis in exercising muscle) 2) Glycerol (from breakdown of TG’s in adipose tissue) 3) Amino Acids (mainly alanine)
• 1) G6-phosphotase, 2) Fructose 1,6-BP 3) Phosphoenolpyruvate carboxykinse (PEPCK)

Question 9

How is gluconeogenesis regulated?

Answer 9

• 2 key enzymes are regulated (F1,6-BP + PEPCK)
• Glucagon (starvation) + cortisol (stress) increase activity of these enzymes stimulating gluconeogenesis
• Insulin decreases activity of both enzymes to inhibit gluconeogenesis.

Question 10

Describe the time course of glucose utilisation.

Answer 10

1) Glucose from food sufficient for - 2 hours
2) Glycogenolysis - for 8-10 hours
3) Gluconeogenesis - from 8-10 hours onwards

Question 11

Describe how and why TG’s are stored

When are TG’s utilised + what kind of control is this under?

Answer 11

• Energy intake in excess is converted in TG’s for storage
• TG’s are hydrophobic and stored as anhydrous form in adipose tissue
• Utilised in prolonged exercise, stress, starvation or during pregnancy - under hormonal control.

Question 12

Describe the structure of adipocytes.

How does weight of adipocytes increase in obesity?

Answer 12

• Adipocytes have large lipid droplets in centre so appear white, with cytoplasm and organelles pushed to the edge. 0.1mm in diameter.
• Can increase in size x4, before dividing to increase total number of cells.

Question 13

Give an overview of dietary TG metabolism

Answer 13

1) Pancreatic lipases in SI breakdown TG’s into fatty acids + glycerol
2) These are recombined to form TG’s in intestinal epithelial cells, and carried by chylomicrons in the blood
3) Chylomicrons carry TG’s to adipose tissue for storage, or to tissues for oxidation of FA’s and utilisation for energy.
4) TG’s stored in adipose tissue (as we know) is stimulated for mobilisation by glucagon and adrenaline for utilisation in tissues.

Question 14

Where and how does fatty acid synthesis (lipogenesis) occur?

Answer 14

• Mainly in liver
• Pyruvate from glycolysis enters mitochondria to form AcetylCoA + OAA which condense to form citrate (in TCA cycle)
• Acetyl-CoA carboxylase produced malonyl-CoA from Acetyl-CoA
• Fatty acid synthase complex builds fatty acids by addition of 2xC’s provided by malonyl-CoA.

Question 15

Describe the process of fat mobilisation (lipolysis)

Answer 15

• Hormone sensitive lipase breaks down TG’s into glycerol + FA’s
• Glycerol travels to liver to be used in gluconeogenesis, FA’s travel complexed with albumin for utilisation in tissues.
• Glucagon + adrenaline cause phosphorylation and activation of hormone sensitive lipase
• Insulin causes dephosphorylation and inhibition