Glycogenolysis, Lipolysis and Gluconeogenesis (early fasting stage)

Question 1

outline fuel sources in body

Answer 1

1. Glycogen Stores:
   Location: Found primarily in the liver and muscles.
2. Adipose Tissue (Body Fat)
3. Muscle Protein
4. Regulatory Hormones

Question 2

Describe the general principles of whole-body glucose homeostasis

Answer 2

Pancreas: Produces insulin (lowers blood glucose) and glucagon (raises blood glucose).

Role of Muscles and Adipose Tissue:
Adipose tissue:
- increase glucose uptake
- == Stimulate lipogenesis (make fat) and glucose oxidation
- decrease lipolysis

Skeletal muscle
- increase glucose uptake

Liver
- increase glucose uptake
- increase glycogenesis
– Decrease Gluconeogenesis

Question 3

Predict the changes in blood glucose during the first few hours of a fast

Answer 3

– During the first few hours, the tissues are using glucose
– So blood glucose concentration falls
– To prevent hypoglycemia, liver releases glucose into the bloodstream
– Thus [glucose]blood stays constant – or at least euglycemic at ~4 mM

Question 4

How glycogen is mobilised from the liver

Answer 4

Glycogen Mobilisation - Glycogenolysis
1) phosphorylase breaks glycogen –> Glucose-1-phosphate
2) G 1-P rapidly converted into G 6-P
3) G6-P in liver cells = G6Pase further processes G6-P to produce free glucose
4) glucose exits through GLUT-9 into blood stream
5) blood glucose levels increases

Question 5

how is glycogen mobilised regulated : Phosphorylase Activation by Glucagon

Answer 5

1) glucagon binds on receptors
2) activates adenylate cyclase, ATP–> cAMP (secondary messenger)
3) cAMP activates protein kinase A (PKA) within the hepatocytes.
4) PKA phosphorylates phosphorylase kinase.
5) Phosphorylase kinase phosphorylates and activates glycogen phosphorylase.
6) Glycogen phosphorylase catalyzes the breakdown of glycogen into glucose-1-phosphate/G-1-P units.

Question 6

why can’t muscle contribute to blood glucose

Answer 6

• muscle cells have no glucagon receptors
• no G6Pase : cannot convert G6P to glucose.

INSTEAD:
breaks down glycogen using the debranching enzyme
–> can breaks the branch points in the glycogen molecule using water (hydrolysis)
–> will break the glycosidic linkages in the glycogen structure.
= release of individual glucose residues from the glycogen chain.
- the debranching enzyme does not use phosphate groups for these hydrolytic reactions.

muscle cells are selfish, use the glucose for own energy needs = local energy needs

In situations where oxygen availability is limited, cells may inhibit PDH (enzyme pyruvate dehydrogenase)
–> G6P makes pyruvate which produces lactate instead
–> lactate can then be released into the bloodstream.
= serve as a substrate for gluconeogenesis in the liver

Question 7

Glycogen Depletion

Answer 7

We need to maintain euglycemia (healthy glucose levels)
– But glycogen store in liver (100 g)
inadequate
– Brain will use it up in < 24 hr

If we want to keep our blood glucose levels at 4-5 mM, we cannot rely only on liver glycogen.

use alternative fuels e.g. FAT
Stimulation of fat breakdown in white adipose tissue e.g. FAT –> fatty acids

Question 8

White Adipose Tissue Lipolysis

Answer 8

1) Glucagon binds to its receptors on the surface of adipocytes (fat cells).
2) Activates an enzyme called adenylyl cyclase = ATP to cyclic AMP (cAMP).
3) cAMP levels activate protein kinase A (PKA)
4) PKA phosphorylates Hormone-Sensitive Lipase (HSL), activating it.
5) PKA also phosphorylates perilipin (acts as a shell which surrounds fat vacuoles)
6) perilipin –> undergoes conformational changes = activated HSL to interact with the lipid droplet.
7) HSL : breakdown of triglycerides into glycerol and free fatty acids.
8) Lots of fatty acids released into the bloodstream

Question 9

Effect of Fatty acid oxidation

Answer 9

• 1) Fatty acids (FAs) are oxidized to produce acetyl CoA.
• 2) Acetyl CoA can enters the Krebs Cycle in the mitochondria.
• 3) PDH can then be inhibited (stop pyruvate –> acetyl CoA) to avoid glucose oxidation and preserve glucose
• GLUT-1 transporters still present = uptake of glucose by muscle cells
• any glucose that may be oxidised into pyruvate –> lactate which can be recycled at liver so glucose preserved

Question 10

inhibition of PDH

Answer 10

Inhibition of PDH
* Acetyl-CoA activates PDH kinase.
* PDH kinase phosphorylates PDH, making it inactive.
(Phosphorylation is the “off” switch for PDH)

Activation of PDH
* Insulin opposes PDH kinase activity.

PDH is interesting, when its phosphorylated, instead of becoming active like other enzymes, its inactive now. hahaha

Question 11

cori cycle

Answer 11

In the absence of PDH activity, pyruvate is converted to lactate.
Lactate is transported to the liver, where it is converted back into glucose through gluconeogenesis.
Glucose is released into the bloodstream, making it available for use by various tissues, including the muscle.